Compound having tgfbeta inhibitory activity and pharmaceutical composition comprising the same

ABSTRACT

The present invention provides compounds represented by formula (I) and pharmaceutically acceptable salts and solvates thereof: 
     
       
         
         
             
             
         
       
     
     wherein X represents CH or N; Z represents —O—, —NH— or —C(═O)—; R and R′ represent a hydrogen atom, hydroxyl, a halogen atom, optionally substituted alkyl, optionally substituted alkenyl optionally substituted alkoxy, amino, aminocarbonyl, or an optionally substituted heterocyclic group; and A represents an optionally substituted specific carbocyclic or heterocyclic group. The compounds according to the present invention have excellent TGFβ inhibitory activity.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to compounds having TGFβ inhibitoryactivity and more particularly to quinoline derivatives and quinazolinederivatives having TGFβ inhibitory activity. The present invention alsorelates to a pharmaceutical composition useful for the prophylaxis ortherapy of diseases for which TGFβ inhibition is effectivetherapeutically.

2. Background Art

TGFβ (transforming growth factor-β) is a cytokine which is veryimportant to organisms for regulating growth differentiation of cellsand repair and regeneration of cells after tissue disorder. Disruptionof its signal is known to cause onset and progression of variousdiseases.

The relationship between TGFβ and fibrosis of organs or tissues is wellknown. The fibrosis of an organ or a tissue takes place as a result ofexcessive accumulation of extracellular matrix proteins within the organfor repair or as a defence mechanism upon damage to the organ or thelike by some cause. The extracellular matrix proteins refer to asubstance surrounding cells of the tissue. For example, fibroticproteins such as collagen and elastin, glycoconjugates such asproteoglycan, and glycoproteins such as fibronectin and laminin isincluded as major extracellular matrix proteins.

When the level of fibrosis of an organ is low, the organ can berecovered to a normal state without leaving any scar. On the other hand,when the level of lesion of the organ is large or when the lesioncontinues, the fibrosis causes damage to the innate function of theorgan. Further, the damage causes new fibrosis to create a viciouscycle. Ultimately, this causes organ failure and, in the worst case,sometimes leads to death.

TGFβ is known to play an important role in the accumulation of theextracellular matrix proteins.

For example, the administration of TGFβ to normal animals is known tocause fibrosis in various tissues (International Review of ExperimentalPathology, 34B: 43-67, 1993). Further, fibrosis of tissues is alsoobserved in the TGFβ1-highly expressing transgenic mice, and in thenormal animals transduced TGFβ1 gene locally (Proc. Natl. Acad. Sci.USA, 92: 2572-2576, 1995; Laboratory Investigation, 74: 991-1003, 1995).

TGFβ is considered to participate in the fibrosis of tissues through thefollowing mechanism.

1) TGFβ strongly induces mRNA expression of extracellular matrixproteins such as fibronectin (Journal of Biological Chemistry, 262:6443-6446, 1987), collagen (Proc. Natl. Acad. Sci. USA, 85 1105-1108,1988), and proteoglycan (Journal of Biological Chemistry, 263:3039-3045, 1988) in cells.

2) TGFβ lowers the expression of an extracellular degradative enzyme forextracellular matrix proteins (Journal of Biological Chemistry, 263:16999-17005, 1988) and, in addition, highly promotes the expression ofan inhibitor of the extracellular matrix degradative enzyme (CancerResearch, 49: 2553-2553, 1989). Consequently, the degradation of theextracellular matrix proteins is suppressed.

3) Further, TGFβ increases the expression of integrin as a receptor ofextracellular matrix proteins and promotes the deposition of theextracellular matrix proteins around cells (Journal of BiologicalChemistry, 263: 4586-4592, 1988).

4) Furthermore, TGFβ proliferates cells which produce extracellularmatrix proteins, such as fibroblast cells (American Journal ofPhysiology, 264: F199-F205, 1993).

TGFβ is known to be mainly involved in the fibrosis of organs such askidney, liver, lung, heart, bone marrow, and skin.

For example, the analysis of expression of TGFβ1 clearly demonstrate anincrease in expression of TGFβ1 in diseases such as human acute renaldiseases, chronic renal diseases, diabetic nephropathy, renal allograftrejection, HIV nephropathy, hepatic fibrosis, cirrhosis, pulmonaryfibrosis, scleroderma, and keloid (New Engl. J. Med., 331, 1286-1292,1994), and the correlation between the TGFb1 expression and theextracellular matrix protein expression.

Further, in pathologic animal models, such as renal failure diseases,diabetic nephropathy, hepatic fibrosis, pulmonary fibrosis, andscleroderma, it is reported that the administration of soluble receptorcomprising the extracellular region of type II receptor andTGFβ-neutralizing antibody can inhibit fibrosis and can improve thepathology (Nature, 346: 371-374, 1990; Journal of the British ThoracicSociety, 54: 805-812, 1999; Journal of Immunology, 163: 5693-5699, 1999;Human Gene Therapy, 11: 33-42, 2000; Proc. Natl. Acad. Sci. USA., 97:8015-20, 2000).

These facts show that the inhibition of TGFβ is useful for theprophylaxis and therapy against all diseases involving fibrosisincluding chronic renal diseases.

Further, TGFβ is also involved in restenosis and arteriosclerosis.

In restenosis model animals, an increase in expression of TGFβ1 and itsreceptor is observed in a injured blood vessel, and TGFβ1 is suggestedto be involved in the formation of new intima after balloon injury issuggested (Clinical and Experimental Pharmacology and Physiology 23:193-200, 1996).

In arteriosclerosis, a highly expression of TGFβ1 is observed innon-foam macrophage infiltrated in an affected region in which matrixproteins synthesis strongly takes place, (American Journal of Physiology146: 1140-1149, 1995), suggesting that the non-foam macrophageparticipates in matrix protein synthesis in an arteriosclerosis affectedregion through TGFβ1.

Further, in a cell-migration test, TGFβ1 is also reported to be a potentstimulating factor for migration of smooth muscle cells causative ofarteriosclerosis and vascular restenosis (Biochem Biophys Res Commun.,169: 725-729, 1990).

TGFβ1 is also involved in wound repair.

For example, an experiment using a neutralizing antibody against TGFβ1demonstrates that the inhibition of TGFβ1 suppresses excessive scarafter wound and is useful for functional recovery. Specifically, it isalso known that the administration of a neutralizing antibody againstTGFβ1 or TGFβ2 to rats can suppress scar and promotes dermal cellconstruction via a mechanism of the suppression of dermal fibronectinand collagen deposition and a reduction in the number of monocytes andmacrophages (Journal of Cellular Science 108: 985-1002, 1995). In othertissues, the administration of anti-TGFβ neutralizing antibody improveslesions in a rabbit corneal injury model and a rat gastric ulcer model(Cornea 16: 177-187, 1997; An international Journal of gastroenterology& Hepatology 39: 172-175, 1996).

Further, TGFβ1 is also known to be involved in peritoneal adhesion.

For example, it is suggested that the inhibition of TGFβ is effective insuppressing peritoneal adhesion and subdermal fibrotic adhesion aftersurgery (J. Surg. Res., 65: 135-138, 1996).

A number of articles report that the administration of an anti-TGFβneutralizing antibody or a soluble type II TGFβ receptor to cancerdisease model animals has also beneficial effects on suppression oftumor growth and cancer metastasis (Journal of Clinical Investigation,92: 2569-76, 1993; Clinical Cancer Research 7: 2931-2940, 2001; CancerRes. 59: 2210-6, 1999; Journal of Clinical Investigation 109: 1551-1559,2002; Journal of Clinical Investigation 109: 1607-1615, 2002).

Tumors usually acquire tumor growth capability and metastatic capabilityby inducing angiogenesis on host side and by lowering immunity of thehost side through TGFβ produced by the tumors per se. The suppressionmechanism is based on the evidences that the administration of theanti-TGFβ neutralizing antibody suppress the tumor growth capability andmetastatic capability. Thus, the inhibition of TGFβ is considered to beeffective in suppressing cancer metastasis and cancer cell growth.

It is also reported that an anti-TGFβ1 neutralizing antibody iseffective in in-vitro amplification of hematopoietic stem cells(Experimental Hematology 26: 374-381, 1998). Further, TGFβ1 has growthinhibitory activity against a large variety of cells. Accordingly, theinhibition of TGFβ is expected to be effective in in-vitro amplificationof a large variety of cells including hematopoietic stem cells.

SUMMARY OF THE INVENTION

The present inventors have now found that a certain group of quinolinederivatives and quinazoline derivatives have inhibitory activity againstTGFβ1. The present invention has been made based on such finding.

It is an object of the present invention to provide a compound havingpotent TGFβ inhibitory activity.

According to the present invention, there is provided a compoundrepresented by formula (I) or a pharmaceutically acceptable salt orsolvate thereof:

wherein

X represents CH or N,

Z represents —O—, —NH—, —S—, or —C(═O)—,

R and R′, which may be the same or different, represent

1) a hydrogen atom,

2) a halogen atom,

3) C₁₋₆ alkyl optionally substituted by hydroxyl, a halogen atom, or asaturated or unsaturated five- or six-membered heterocyclic group,

4) C₂₋₆ alkenyl optionally substituted by an oxygen atom or C₁₋₄ alkoxy,

5) amino in which one or two hydrogen atoms on the amino group areoptionally substituted by C₁₋₆ alkyl, and the C₁₋₆ alkyl group isoptionally substituted by hydroxyl or a saturated or unsaturated five-or six-membered carbocyclic or heterocyclic group,

6) —C(═O)—NH₂ wherein one or two hydrogen atoms on the aminocarbonylgroup are optionally substituted by C₁₋₆ alkyl,

7) —OR″ wherein R″ represents a hydrogen atom, or —(CH₂)_(m)—R^(a)wherein R^(a) represents a hydrogen atom, a halogen atom, hydroxyl, asaturated or unsaturated three- to six-membered carbocyclic orheterocyclic group, C₁₋₄ alkoxy, C₁₋₄ alkoxycarbonyl, or —NR^(b)R^(c)wherein R^(b) and R^(c), which may be the same or different, represent ahydrogen atom or C₁₋₆ alkyl, in which the C₁₋₆ alkyl group is optionallysubstituted by hydroxyl, an oxygen atom, amino, a nitrogen atom, or C₁₋₄alkyl, and R^(b) and R^(c) may combine with a nitrogen atom attachedthereto to form a saturated or unsaturated five- or six-memberedheterocyclic group, which may further comprise one or more heteroatoms,and in which the heterocyclic group is optionally substituted by C₁₋₄alkyl, optionally substituted by hydroxyl, hydroxyl, an oxygen atom,aminocarbonyl, C₁₋₄ alkoxy, C₁₋₄ alkoxycarbonyl, or a saturated orunsaturated five- or six-membered heterocyclic group, and theheterocyclic group may condense with another saturated or unsaturatedfive- or six-membered carbocyclic or heterocyclic group to form abicyclic group; m is an integer of 1 to 6; and the alkyl chain part inthis group, —(CH₂)_(m)—, is optionally substituted by hydroxyl, anoxygen atom, —OR^(d) group, wherein R^(d) represents C₁₋₄ alkyl or C₁₋₄alkylcarbonyl, or C₁₋₄ alkyl optionally substituted by hydroxyl or ahalogen atom, or

8) a saturated or unsaturated five- or six-membered heterocyclic group,and

A represents any group selected from the group consisting of formulae(a) to (c):

(a) a group of formula (a):

wherein

R³ to R⁶, which may be the same or different, represent

a hydrogen atom,

hydroxyl,

a halogen atom,

C₁₋₆ alkyl,

C₁₋₁₀ alkoxy optionally substituted by a halogen atom or phenyl,

C₂₋₆ alkenylcarbonyloxy,

C₁₋₄ alkylcarbonyl,

C₁₋₄ alkylthio, or

phenyl optionally substituted by a halogen atom,

R³ and R⁴, R⁴ and R⁵, and R⁵ and R⁶ each may combine with a carbon atomattached thereto to form a saturated or unsaturated five- orsix-membered carbocyclic or heterocyclic group in which the carbocyclicor heterocyclic group is optionally substituted by a hydrogen atom, ahalogen atom, hydroxyl, or C₁₋₄ alkyl,

G represents

—C(═O)—R⁷,

—CH₂—N(—R¹¹)R¹², or

—C(—R¹³) (═NR¹⁴),

wherein

R⁷ represents

a hydrogen atom,

C₁₋₈ alkyl optionally substituted by C₁₋₄ alkoxy, an oxygen atom, or asaturated or unsaturated five- or six-membered carbocyclic group,

C₂₋₆ alkenyl optionally substituted by a saturated or unsaturated five-or six-membered carbocyclic group,

a saturated or unsaturated five- or six-membered carbocyclic group orheterocyclic group in which the carbocyclic or heterocyclic group isoptionally substituted by hydroxyl, C₁₋₄ alkyl, or C₁₋₄ alkoxy, and theC₁₋₄ alkoxy group is optionally substituted by a halogen atom or asaturated or unsaturated five- or six-membered heterocyclic group,

group —O—R⁸, or

group —N(—R⁹)R¹⁰

wherein

R⁸ represents

C₁₋₁₀ alkyl optionally substituted by a saturated or unsaturated five-or six-membered carbocyclic group,

C₂₋₈ alkenyl, or

a saturated or unsaturated five- or six-membered carbocyclic group inwhich the carbocyclic group is optionally substituted by a halogen atom,

R⁹ and R¹⁰, and R¹¹ and R¹², which may be the same or different, eachrepresent

a hydrogen atom,

C₁₋₆ alkyl,

a saturated or unsaturated five- or six-membered carbocyclic group inwhich the carbocyclic group is optionally substituted by a halogen atom,or

naphthyl optionally substituted by a halogen atom,

R⁹ and R¹⁰, or R¹¹ and R¹² may combine with a nitrogen atom attachedthereto to form a saturated or unsaturated five- or six-memberedheterocyclic group which may further comprise one or more heteroatomsand in which the heterocyclic group is optionally substituted by C₁₋₄alkyl optionally substituted by hydroxyl, or a saturated or unsaturatedfive- or six-membered heterocyclic group,

R¹³ represents

a hydrogen atom or

C₁₋₄ alkyl,

R¹⁴ represents

a hydrogen atom,

hydroxyl,

C₁₋₄ alkoxy optionally substituted by a saturated or unsaturatedsix-membered carbocyclic group,

C₂₋₆ alkenyloxy,

phenyloxy, or

amino optionally substituted by a saturated or unsaturated six-memberedheterocyclic group,

(b) a group of formula (b):

wherein

any one of J, L, and M represents a nitrogen atom with the remaining tworepresenting a carbon atom,

R¹⁵ to R¹⁹, which may be the same or different, represent

a hydrogen atom,

a halogen atom,

nitro,

cyano,

C₁₋₆ alkyl in which the alkyl group is optionally substituted byhydroxyl; phenyl; amino optionally substituted by C₁₋₄ alkyl; C₁₋₄alkylcarbonyloxy; or a saturated or unsaturated six-memberedheterocyclic group optionally substituted by C₁₋₄ alkyl,

C₁₋₈ alkoxy,

C₁₋₄ alkylcarbonyl,

C₂₋₆ alkenyl optionally substituted by a saturated or unsaturated five-or six-membered carbocyclic group,

C₂₋₆ alkynyl optionally substituted by C₁₋₄ alkylsilyl,

C₁₋₄ alkylthio,

a saturated or unsaturated three- to eight-membered carbocyclic oxygroup,

a saturated or unsaturated six-membered carbocyclic carbonyl orheterocyclic carbonyl group optionally substituted by C₁₋₄ alkyl, or

a saturated or unsaturated three- to eight-membered carbocyclic orheterocyclic group in which the carbocyclic or heterocyclic group isoptionally substituted by hydroxyl; cyano; a halogen atom; C₁₋₄ alkoxy;phenyloxy; C₁₋₄ alkylcarbonyl; amino optionally substituted by C₁₋₄alkyl or C₁₋₄ alkylcarbonyl; aminocarbonyl optionally substituted byC₁₋₄ alkyl; or C₁₋₄ alkyl optionally substituted by hydroxyl or ahalogen atom,

R¹⁵ and R¹⁶, R¹⁶ and R¹⁷, R¹⁷ and R¹⁸, and R¹⁸ and R¹⁹ each may combinewith a carbon atom attached thereto to form a saturated or unsaturatedfive- or six-membered carbocyclic or heterocyclic group, and thecarbocyclic or heterocyclic group is optionally substituted by C₁₋₄alkyl,

provided that, among R¹⁷ to R¹⁹, those in which J, L, or M attachedthereto is a nitrogen atom are absent, and

(c) a group of formula (c):

wherein

R²⁰ to R²⁴, which may be the same or different, represent

a hydrogen atom,

a halogen atom,

C₁₋₁₀ alkyl optionally substituted by hydroxyl, a saturated orunsaturated five- or six-membered carbocyclic or heterocyclic group,

C₁₋₈ alkoxy,

C₂₋₆ alkenyl optionally substituted by C₁₋₄ alkyl, C₁₋₄ alkoxy, anoxygen atom or phenyl,

phenylcarbonyl optionally substituted by C₁₋₄ alkyl,

amino optionally substituted by phenyl,

nitro, or

a saturated or unsaturated five- or six-membered carbocyclic orheterocyclic group in which the carbocyclic or heterocyclic group isoptionally substituted by C₁₋₆ alkyl,

R²⁰ and R²¹, or R²³ and R²⁴ may combine with a carbon atom attachedthereto to form a saturated or unsaturated five- or six-memberedcarbocyclic or heterocyclic group, and

R²¹ and R²² or R²² and R²³ may combine with a carbon atom attachedthereto to form a saturated or unsaturated five- or six-memberedcarbocyclic or heterocyclic group in which the carbocyclic orheterocyclic group is optionally substituted by a halogen atom, C₁₋₄alkyl, C₁₋₄ alkylcarbonyl, C₁₋₆ alkoxycarbonyl, or an oxygen atom, andthe carbocyclic or heterocyclic group may condense with anothersaturated or unsaturated five- or six-membered carbocyclic orheterocyclic group to form a tricyclic group together with thesix-membered carbocyclic ring of formula (c).

In a preferred embodiment of the present invention, the compoundaccording to the present invention is a compound represented by formula(II), or a pharmaceutically acceptable salt or solvate thereof:

wherein

X, Z, and A are as defined above,

R¹ and R², which may be the same or different, represent a hydrogenatom, or —(CH₂)_(m)—R^(a) wherein R^(a) represents a hydrogen atom, ahalogen atom, hydroxyl, a saturated or unsaturated three- tosix-membered carbocyclic or heterocyclic group, C₁₋₄ alkoxy, C₁₋₄alkoxycarbonyl, or —NR^(b)R^(c) wherein R^(b) and R^(c), which may bethe same or different, represent a hydrogen atom or C₁₋₆ alkyl, in whichthe C₁₋₆ alkyl group is optionally substituted by hydroxyl, an oxygenatom, amino, a nitrogen atom, or C₁₋₄ alkyl, and R^(b) and R^(c) maycombine with a nitrogen atom attached thereto to form a saturated orunsaturated five- or six-membered heterocyclic group, which may furthercomprise one or more heteroatoms, and in which the heterocyclic group isoptionally substituted by C₁₋₄ alkyl, optionally substituted byhydroxyl, hydroxyl, an oxygen atom, aminocarbonyl, C₁₋₄ alkoxy, C₁₋₄alkoxycarbonyl, or a saturated or unsaturated five- or six-memberedheterocyclic group, and the heterocyclic group may condense with anothersaturated or unsaturated five- or six-membered carbocyclic orheterocyclic group to form a bicyclic group; m is an integer of 1 to 6;and the alkyl chain part in this group, —(CH₂)_(m)—, is optionallysubstituted by hydroxyl, an oxygen atom, —OR^(d) group, wherein R^(d)represents C₁₋₄ alkyl or C₁₋₄ alkylcarbonyl, or C₁₋₄ alkyl optionallysubstituted by hydroxyl or a halogen atom.

The compound according to the present invention can be used for thetherapy or prophylaxis of diseases for which TGFβ inhibition iseffective therapeutically or prophylactically.

Diseases for which TGFβ inhibition is effective therapeutically orprophylactically include, for example, chronic renal disease, acuterenal disease, hepatic fibrosis, cirrhosis, fibroid lung, scleroderma,wound healing, arthritis, congestive cardiac disease, ulcer, oculardisorder, cornea disorder, diabetic nephropathy, peritoneal sclerosis,arterial sclerosis, peritoneal adhesion, and subdermal adhesion and,further, malignant tumors. Accordingly, the compound according to thepresent invention is useful for the prophylaxis or therapy of suchdiseases. The compound according to the present invention is also usefulfor in-vitro amplification of hematopoietic stem cells.

The pharmaceutical composition according to the present inventioncomprises as an active ingredient the compound represented by formula(I) according to the present invention.

The TGFβ inhibitor according to the present invention comprises thecompound according to the present invention.

The method for treating or preventing a disease for which TGFβinhibition is effective therapeutically or prophylactically according tothe present invention comprises the step of administering atherapeutically or prophylactically effective amount of the compoundrepresented by formula (I) according to the present invention or apharmaceutically acceptable salt or solvate thereof to a patient whoshould undergo therapy of a disease for which TGFβ inhibition iseffective therapeutically or prophylactically.

The method for amplifying cells in vitro according to the presentinvention comprises the step of administering, to target cells in vitro,the compound represented by formula (I) according to the presentinvention or a pharmaceutically acceptable salt or solvate thereof in anamount effective for promoting cell amplification to amplify cells.

DETAILED DESCRIPTION OF THE INVENTION Compound of Formula (I)

The terms “alkyl,” “alkoxy,” “alkenyl,” and “alkynyl” as used herein asa group or a part of a group respectively mean straight chain orbranched chain alkyl, alkoxy, alkenyl, and alkynyl.

The terms “alkylcarbonyl,” “alkylsilyl,” “alkylthio,” “alkoxycarbonyl,”“alkenylcarbonyloxy,” and “alkenyloxy” as used herein as a group or apart of a group respectively mean straight chain or branched chainalkylcarbonyl, alkylsilyl, alkylthio, alkoxycarbonyl,alkenylcarbonyloxy, and alkenyloxy.

Accordingly, for example, the “C₁₋₁₀ alkyl” and “C₁₋₁₀ alkoxy” as usedherein as a group or a part of a group respectively mean straight chainor branched chain alkyl and alkoxy having 1 to 10 carbon atoms.

“C₁₋₁₀ alkyl” is preferably C₁₋₈ alkyl, more preferably C₁₋₆ alkyl,still more preferably C₁₋₄ alkyl. “C₁₋₈ alkyl” is preferably C₁₋₆ alkyl,more preferably C₁₋₄ alkyl. “C₁₋₆ alkyl” is preferably C₁₋₄ alkyl, morepreferably C₁₋₂ alkyl. “C₁₋₄ alkyl” is preferably C₁₋₂ alkyl.

“C₁₋₁₀ alkoxy” is preferably C₁₋₈ alkoxy, more preferably C₁₋₆ alkoxy,still more preferably C₁₋₄ alkoxy. “C₁₋₈ alkoxy” is preferably C₁₋₆alkoxy, more preferably C₁₋₄ alkoxy. “C₁₋₄ alkoxy” is preferably C₁₋₂alkoxy.

“C₂₋₈ alkenyl” is preferably C₂₋₆ alkenyl, more preferably C₂₋₄ alkenyl.“C₂₋₆ alkenyl” is preferably C₂₋₄ alkenyl. “C₂₋₄ alkenyl” is preferablyC₂ or C₃ alkenyl, more preferably C₂ alkenyl.

“C₂₋₆ alkynyl” is preferably C₂₋₄ alkynyl.

“C₁₋₄ alkylcarbonyl” is preferably C₁₋₂ alkylcarbonyl.

“C₁₋₄ alkylsilyl” is preferably C₁₋₂ alkylsilyl.

“C₁₋₄ alkylthio” is preferably C₁₋₂ alkylthio.

“C₁₋₆ alkoxycarbonyl” is preferably C₁₋₄ alkoxycarbonyl, more preferablyC₁₋₂ alkoxycarbonyl.

“C₂₋₆ alkenylcarbonyloxy” is preferably C₂₋₄ alkenylcarbonyloxy.

“C₂₋₆ alkenyloxy” is preferably C₂₋₄ alkenyloxy.

Examples of C₁₋₁₀ alkyl include methyl, ethyl, n-propyl, isopropyl,n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, n-hexyl, n-heptyl,n-octyl, n-nonyl, and n-decyl.

Examples of C₁₋₁₀ alkoxy include methoxy, ethoxy, n-propoxy, i-propoxy,n-butoxy, i-butoxy, s-butoxy, and t-butoxy.

Examples of C₂₋₆ alkenyl include allyl, butenyl, pentenyl, and hexenyl.

Examples of C₂₋₆ alkynyl include 2-propynyl, butynyl, pentynyl, andhexynyl.

Examples of C₁₋₄ alkylcarbonyl include aldehyde, methylcarbonyl,ethylcarbonyl, n-propylcarbonyl, isopropylcarbonyl, n-butylcarbonyl,i-butylcarbonyl, and s-butylcarbonyl.

Examples of C₁₋₄ alkylsilyl include methylsilyl, ethylsilyl,n-propylsilyl, isopropylsilyl, n-butylsilyl, i-butylsilyl, ands-butylsilyl.

Examples of C₁₋₄ alkylthio include methylthio, ethylthio, n-propylthio,isopropylthio, n-butylthio, i-butylthio, and s-butylthio.

Examples of C₁₋₆ alkoxycarbonyl include methoxycarbonyl, ethoxycarbonyl,n-propoxycarbonyl, i-propoxycarbonyl, n-butoxycarbonyl,i-butoxycarbonyl, s-butoxycarbonyl, and t-butoxycarbonyl.

Examples of C₂₋₆ alkenylcarbonyloxy include allylcarbonyloxy,butenylcarbonyloxy, pentenylcarbonyloxy, and hexenylcarbonyloxy.

Examples of C₂₋₆ alkenyloxy include allyloxy, butenyloxy, pentenyloxy,and hexenyloxy.

The expression alkyl “optionally substituted by” as used herein refersto alkyl, in which one or more hydrogen atoms on the alkyl group havebeen substituted by one or more substituents which may be the same ordifferent, and unsubstituted alkyl. It will be apparent to a personhaving ordinary skill in the art that the maximum number of substituentsmay be determined depending upon the number of substitutable hydrogenatoms on the alkyl group. This is true of groups, which may besubstituted, other than the alkyl group, for example, alkylsilyl,alkyloxycarbonyl, alkoxy, alkenyl, alkynyl, phenyl, phenylcarbonyl,naphthyl and the like.

The term “halogen atom” as used herein means a fluorine, chlorine,bromine, or iodine atom.

The terms “unsaturated carbocyclic ring” and “unsaturated heterocyclicring” as used herein respectively mean carbocyclic and heterocyclicrings having one or more unsaturated bonds such as a double bond.

The “saturated or unsaturated three- to eight-membered carbocyclic ring”is preferably a four- to seven-membered, more preferably five- orsix-membered, saturated or unsaturated carbocyclic ring. Examples ofsaturated or unsaturated three- to eight-membered carbocyclic ringsinclude phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, andcycloheptyl.

The “saturated or unsaturated three- to eight-membered heterocyclicring” contains at least one hetero-atom selected from oxygen, nitrogen,and sulfur atoms. The saturated or unsaturated three- to eight-memberedheterocyclic ring preferably contains one, two or three hetero-atomswith the remaining ring-constituting atoms being carbon atoms. Thesaturated or unsaturated three- to eight-membered heterocyclic ring ispreferably a saturated or unsaturated four- to seven-memberedheterocyclic ring, more preferably a saturated or unsaturated five- orsix-membered heterocyclic ring. Examples of saturated or unsaturatedthree- to eight-membered heterocyclic groups include thienyl, pyridyl,1,2,3-triazolyl, thiazolyl, imidazolyl, isoxazolyl, pyrazolyl,piperazinyl, piperazino, piperidyl, piperidino, morpholinyl, morpholino,homopiperazinyl, homopiperazino, thiomorpholinyl, thiomorpholino,tetrahydropyrrolyl, and azepanyl.

The saturated or unsaturated carboxylic and heterocyclic groups maycondense with another saturated or unsaturated five- to seven-memberedcarbocyclic or heterocyclic ring to form a bicyclic group, preferably asaturated or unsaturated nine- to twelve-membered bicyclic carbocyclicor heterocyclic group. Such bicyclic groups include naphthyl, quinolyl,1,2,3,4-tetrahydroquinolyl, 1,4-benzoxanyl, indanyl, indolyl,1,2,3,4-tetrahydronaphthyl, and phthalimide.

When the carbocyclic or heterocyclic group is substituted by two C₁₋₆alkyl groups, the two alkyl groups may combine together to form analkylene chain, preferably a C₁₋₃ alkylene chain. Carbocyclic orheterocyclic groups having this crosslinked structure includeazabicyclo[2.2.2]octanyl, bicyclo[2.2.2]octanyl and norbornanyl.

The “saturated or unsaturated five- to six-membered carbocyclic group”as used herein preferably has a six-membered saturated or unsaturatedcarbocyclic ring. Examples of saturated or unsaturated five- orsix-membered carbocyclic rings include phenyl, cyclopentyl, andcyclohexyl.

The “saturated or unsaturated five- or six-membered heterocyclic group”as used herein refers to a saturated or unsaturated five- orsix-membered monocyclic heterocyclic group. That is, the saturated orunsaturated five- or six-membered heterocyclic ring may be aheterocyclic ring that contains one to three, preferably one or twohetero-atoms with the remaining ring-constituting atoms being carbonatoms. The heterocyclic group contains at least one hetero-atom selectedfrom oxygen, nitrogen, and sulfur atoms. Examples of heterocyclic groupsinclude pyridyl, furyl, thienyl, pyrrolyl, pyridazyl, pyrimidyl,morpholinyl, morpholino, isoxazolyl, oxazolyl, thiazolyl, imidazoyl,isothiazolyl, and pyrazyl.

This heterocyclic group is optionally substituted by C₁₋₆ alkyl; C₁₋₄alkyl optionally substituted by hydroxyl; or a saturated or unsaturatedfive- or six-membered heterocyclic group, so far as there is noparticular description on the substituent.

The “saturated or unsaturated six-membered carbocyclic oxy group” asused herein include phenyloxy and cyclohexyloxy.

The “saturated or unsaturated five- or six-membered carbocyclic carbonylgroup” as used herein preferably has a saturated or unsaturatedsix-membered carbocyclic ring. Examples of saturated or unsaturatedfive- or six-membered carbocyclic carbonyl groups includephenylcarbonyl, cyclopentylcarbonyl, and cyclohexylcarbonyl.

The “saturated or unsaturated five- or six-membered heterocycliccarbonyl group” as used herein refers to a carbonyl group containing asaturated or unsaturated five- or six-membered monocyclic heterocyclicgroup. That is, the heterocyclic group part in the saturated orunsaturated five- or six-membered heterocyclic carbonyl group may be aheterocyclic ring that contains one to three, preferably one or twohetero-atoms with the remaining ring-constituting atoms being carbonatoms. The heterocyclic group contains at least one hetero-atom selectedfrom oxygen, nitrogen, and sulfur atoms. Examples of heterocycliccarbonyl groups include pyridylcarbonyl, furylcarbonyl, thienylcarbonyl,pyrrolylcarbonyl, pyridazylcarbonyl, pyrimidylcarbonyl,morpholinylcarbonyl, morpholinocarbonyl, isoxazolylcarbonyl,oxazolylcarbonyl, thiazolylcarbonyl, imidazoylcarbonyl,isothiazolylcarbonyl, and pyrazylcarbonyl.

In one preferred embodiment of the present invention, at least one of Rand R′ is selected from the group consisting of

1) a hydrogen atom,

2) a halogen atom,

3) C₁₋₆ alkyl optionally substituted by hydroxyl, a halogen atom, or asaturated or unsaturated five- or six-membered heterocyclic group,

4) C₂₋₆ alkenyl optionally substituted by an oxygen atom or C₁₋₄ alkoxy,

5) amino in which one or two hydrogen atoms on the amino group areoptionally substituted by C₁₋₆ alkyl, and the C₁₋₆ alkyl group isoptionally substituted by hydroxyl or a saturated or unsaturated five-or six-membered carbocyclic or heterocyclic group,

6) —C(═O)—NH₂ wherein one or two hydrogen atoms on the aminocarbonylgroup are optionally substituted by C₁₋₆ alkyl, or

8) a saturated or unsaturated five- or six-membered heterocyclic group.

In a more preferred embodiment of the present invention, at least one ofR and R′ is selected from the group consisting of a hydrogen atom,

a halogen atom,

C₁₋₄ alkyl optionally substituted by hydroxyl, a halogen atom, or asaturated or unsaturated five- or six-membered heterocyclic group,

C₂₋₄ alkenyl optionally substituted by an oxygen atom or C₁₋₄ alkoxy,

amino in which one or two hydrogen atoms on the amino group areoptionally substituted by C₁₋₄ alkyl, and the C₁₋₄ alkyl group isoptionally substituted by hydroxyl or a saturated or unsaturated five-or six-membered heterocyclic group,

—C(═O)—NH₂, and

a saturated or unsaturated five- or six-membered heterocyclic group.

In a still more preferred embodiment of the present invention, R′ isselected from the group consisting of

a hydrogen atom,

a halogen atom,

C₁₋₄ alkyl optionally substituted by hydroxyl, a halogen atom, or asaturated or unsaturated five- or six-membered heterocyclic group,

C₂₋₄ alkenyl optionally substituted by an oxygen atom or C₁₋₄ alkoxy,

amino in which one or two hydrogen atoms on the amino group areoptionally substituted by C₁₋₄ alkyl, and the C₁₋₄ alkyl group isoptionally substituted by hydroxyl or a saturated or unsaturated five-or six-membered heterocyclic group,

—C(═O)—NH₂, and

a saturated or unsaturated five- or six-membered heterocyclic group.

In another more preferred embodiment of the present invention, at leastone of R and R′ is selected from the group consisting of

a hydrogen atom,

a halogen atom,

C₁₋₄ alkyl optionally substituted by hydroxyl, a halogen atom, or asaturated six-membered heterocyclic group,

C₂₋₄ alkenyl optionally substituted by an oxygen atom or C₁₋₄ alkoxy,

amino in which one of the hydrogen atoms on the amino group isoptionally substituted by C₁₋₄ alkyl, and the C₁₋₄ alkyl group isoptionally substituted by a saturated six-membered heterocyclic group,and

an unsaturated six-membered heterocyclic group.

In another preferred embodiment of the present invention, R isrepresented by —OR¹, and R′ is represented by —OR². In this case, R¹ andR², which may be the same or different, represent a hydrogen atom, or—(CH₂)_(m)—R^(a) wherein R^(a) represents a hydrogen atom, a halogenatom, hydroxyl, a saturated or unsaturated three- to six-memberedcarbocyclic or heterocyclic group, C₁₋₄ alkoxy, C₁₋₄ alkoxycarbonyl, or—NR^(b)R^(c) wherein R^(b) and R^(c), which may be the same ordifferent, represent a hydrogen atom or C₁₋₆ alkyl, in which the C₁₋₆alkyl group may be substituted by hydroxyl, an oxygen atom, amino, anitrogen atom, or C₁₋₄ alkyl, and R^(b) and R^(c) may combine with anitrogen atom attached thereto to form a saturated or unsaturated five-or six-membered heterocyclic group, which may further comprise one ormore heteroatoms, and in which the heterocyclic group is optionallysubstituted by C₁₋₄ alkyl optionally substituted by hydroxyl, hydroxyl,an oxygen atom, aminocarbonyl, C₁₋₄ alkoxy, C₁₋₄ alkoxycarbonyl, or asaturated or unsaturated five- or six-membered heterocyclic group, andthe heterocyclic group may condense with another saturated orunsaturated five- or six-membered carbocyclic or heterocyclic group toform a bicyclic group; m is an integer of 1 to 6; and the alkyl chainpart in this group, —(CH₂)_(m)—, is optionally substituted by hydroxyl,an oxygen atom, —OR^(d) group, wherein R^(d) represents C₁₋₄ alkyl orC₁₋₄ alkylcarbonyl, or C₁₋₄ alkyl optionally substituted by hydroxyl ora halogen atom.

Specifically, in a preferred embodiment of the present invention, thecompound represented by formula (I) is represented by formula (II).

In R^(a) in R″, R¹ or R², the “saturated or unsaturated three- tosix-membered carbocyclic group” is preferably a saturated or unsaturatedsix-membered carbocyclic group.

In R^(a) in R″, R¹ or R², the “saturated or unsaturated three- tosix-membered heterocyclic group” contains at least one heteroatomselected from oxygen, nitrogen, and sulfur atoms, preferably an oxygenor nitrogen atom. Preferably, the saturated or unsaturated three- tosix-membered heterocyclic group may be a heterocyclic group whichcontains one or two heteroatoms with the remaining ring atoms being acarbon atom.

In still another preferred embodiment of the present invention, R¹ andR² represent a hydrogen atom, or —(CH₂)_(m)—R^(a) wherein R^(a)represents a hydrogen atom, a halogen atom, hydroxyl, a saturated orunsaturated three- to six-membered carbocyclic or heterocyclic group, or—NR^(b)R^(c) wherein R^(b) and R^(c), which may be the same ordifferent, represent a hydrogen atom or C₁₋₆ alkyl optionallysubstituted by hydroxyl, and R^(b) and R^(c) may combine with a nitrogenatom attached thereto to form a saturated or unsaturated five- orsix-membered heterocyclic group, which may further comprise one or moreheteroatoms, and in which the heterocyclic group is optionallysubstituted by C₁₋₄ alkyl optionally substituted by hydroxyl, or asaturated or unsaturated five- or six-membered heterocyclic group; m isan integer of 1 to 5; and the alkyl chain part in this group,—(CH₂)_(m)—, is optionally substituted by hydroxyl, an oxygen atom, or—OR^(d) group, wherein R^(d) represents C₁₋₄ alkyl or C₁₋₄alkylcarbonyl.

In a preferred embodiment of the present invention, R¹ and R², which maybe the same or different, represent any group selected from the groupconsisting of

a hydrogen atom,

C₁₋₆ alkyl optionally substituted by phenyl, and

groups of formulae (I) to (vi):

(i) a group of formula (i):

wherein

R⁵¹ and R⁵², which may be the same or different, represent

a hydrogen atom, or

C₁₋₈ alkyl optionally substituted by hydroxyl, an oxygen atom, amino, ora nitrogen atom,

R⁵¹ and R⁵² may combine with a nitrogen atom attached thereto to form asaturated or unsaturated five- or six-membered heterocyclic group whichmay further comprise one or more heteroatoms and in which theheterocyclic group is optionally substituted by C₁₋₄ alkyl optionallysubstituted by hydroxyl, hydroxyl, an oxygen atom, aminocarbonyl, C₁₋₄alkoxy, C₁₋₄ alkoxycarbonyl, or a saturated or unsaturated five- orsix-membered heterocyclic group, and the heterocyclic group optionallyformed by allowing R⁵¹ to combine with R⁵² may condense with anothersaturated or unsaturated five- or six-membered carbocyclic orheterocyclic group to form a bicyclic group,

p is an integer of 2 to 4, preferably 2 or 3, and

the alkyl chain part in this group is optionally substituted byhydroxyl, or —OR^(e) group wherein R^(e) represents C₁₋₄ alkyl or C₁₋₄alkylcarbonyl,

(ii) a group of formula (ii):

wherein q is an integer of 1 to 4, preferably 1 or 2,

(iii) a group of formula (iii):

wherein Hal represents a halogen atom, preferably a fluorine or chlorineatom, and

r represents an integer of 2 to 4, preferably 2 or 3,

(iv) a group of formula (iv):

wherein

R⁵³ and R⁵⁴, which may be the same or different, represent

a hydrogen atom, or

C₁₋₆ alkyl optionally substituted by hydroxyl,

R⁵³ and R⁵⁴ may combine with a nitrogen atom attached thereto to form asaturated or unsaturated five- or six-membered heterocyclic group whichmay further comprise one or more heteroatoms and in which theheterocyclic group is optionally substituted by C₁₋₄ alkyl, optionallysubstituted by hydroxyl, or a saturated or unsaturated five- orsix-membered heterocyclic group, and the heterocyclic group optionallyformed by allowing R⁵³ to combine with R⁵⁴ may condense with anothersaturated or unsaturated five- or six-membered carbocyclic orheterocyclic group to form a bicyclic group, and

s is an integer of 0 to 3, preferably 0 to 2,

(v) a group of formula (v):

wherein

R⁵⁵ represents C₁₋₄ alkyl and

t is an integer of 0 (zero) to 3, preferably 0 to 2, and

(vi) a group of formula (vi):

wherein

R⁵⁶, R⁵⁷ and R⁵⁸, which may be the same or different, represent

a hydrogen atom,

C₁₋₄ alkoxycarbonyl, or

C₁₋₄ alkyl optionally substituted by hydroxyl or a halogen atom, and

u is an integer of 0 (zero) to 4, preferably 0 to 2, more preferably 0or 1.

In a more preferred embodiment of the present invention, formula (i) isrepresented by formula (i-a):

In a still more preferred embodiment of the present invention, R¹ andR², which may be the same or different, represent

any group selected from the group consisting of

a hydrogen atom,

C₁₋₆ alkyl,

benzyl,

groups of formulae (i), (v), and (vi), and

groups of formulae (ii-a), (iii-a), and (iv-a):

-   -   formula (ii-a):

-   -   formula (iii-a):

wherein r1 is an integer of 2 to 4, preferably 2 or 3, and

-   -   formula (iv-a):

In a still more preferred embodiment of the present invention, one of R¹and R² is selected from C₁₋₆ alkyl, and the other substituent isselected from the group consisting of

a hydrogen atom,

benzyl, and

groups of formulae (i), (ii-a), (iii-a), (iv-a), (v), and (vi).

When at least one of R¹ and R² represents a group of formula (i), R⁵¹and R⁵², which may be the same or different, preferably represent

a hydrogen atom, or

C₁₋₄ alkyl optionally substituted by hydroxyl, an oxygen atom, amino, ora nitrogen atom,

R⁵¹ and R⁵² may combine with a nitrogen atom attached thereto to form aheterocyclic group such as pyridyl, pyrrolyl, pyridazyl, 2-piperidyl,piperidino, piperazyl, pyrimidyl, morpholinyl, morpholino, imidazoyl, orpyrazyl, and the heterocyclic group is optionally substituted by C₁₋₄alkyl optionally substituted by hydroxyl, hydroxyl, an oxygen atom,aminocarbonyl, C₁₋₄ alkoxy, C₁₋₄ alkoxycarbonyl, or a saturated five- orsix-membered heterocyclic group. Further, the heterocyclic group formedby allowing R⁵¹ to combine with R⁵² may condense with another saturatedor unsaturated five- or six-membered carbocyclic or heterocyclic groupto form a bicyclic group.

When at least one of R¹ and R² represents a group of formula (i-a), R⁵¹and R⁵², which may be the same or different, preferably represent

a hydrogen atom, or

C₁₋₂ alkyl optionally substituted by hydroxyl, or

R⁵¹ and R⁵² may combine with a nitrogen atom attached thereto to form aheterocyclic group such as 2-piperidyl, piperidino, piperazyl,morpholinyl, morpholino, or imidazoyl. This heterocyclic group isoptionally substituted by methyl optionally substituted by hydroxyl, oris optionally substituted by pyrrolidyl or piperidino.

When at least one of R¹ and R² represents a group of formula (iv-a), R⁵³and R⁵⁴ preferably combine with a nitrogen atom attached thereto to forma saturated or unsaturated five- or six-membered heterocyclic group, inwhich the heterocyclic group may further contain one or moreheteroatoms, more preferably form morpholine.

When at least one of R¹ and R² represents a group of formula (v), R⁵⁵preferably represents methyl or ethyl.

When at least one of R¹ and R² represents a group of formula (vi), R⁵⁶,R⁵⁷, and R⁵⁸, which may be the same or different, preferably represent ahydrogen atom, C₁₋₂ alkoxycarbonyl, or C₁₋₄ alkyl optionally substitutedby hydroxyl. When any of R⁵⁶, R⁵⁷, and R⁵⁸ represents C₁₋₄ alkyl, thealkyl group is optionally substituted by one or two hydroxyl groups.

In a preferred embodiment of the present invention, at least one of R¹and R² represents C₁₋₆ alkyl. More preferably, R¹ represents C₁₋₆ alkyl.

When at least one of R¹ and R² represents C₁₋₆ alkyl, the C₁₋₆ alkylgroup preferably represents C₁₋₄ alkyl, more preferably methyl or ethyl,most preferably methyl.

In formula (I), the group of formula (a), which A may represent, ispreferably represented by any group selected from the group consistingof formulae (a1) to (a3):

(1) a group of formula (a1):

wherein

R³, R⁴ and R⁶, which may be the same or different, represent

a hydrogen atom,

a halogen atom,

C₁₋₆ alkyl,

C₁₋₁₀ alkoxy optionally substituted by a halogen atom or phenyl,

C₂₋₆ alkenylcarbonyloxy,

C₁₋₄ alkylcarbonyl, or

phenyl optionally substituted by a halogen atom,

R⁵ is as defined in formula (a), that is,

a hydrogen atom,

hydroxyl,

a halogen atom,

C₁₋₆ alkyl,

C₁₋₁₀ alkoxy optionally substituted by a halogen atom or phenyl,

C₂₋₆ alkenylcarbonyloxy,

C₁₋₄ alkylcarbonyl,

C₁₋₄ alkylthio, or

phenyl optionally substituted by a halogen atom,

R³ and R⁴, R⁴ and R⁵, and R⁵ and R⁶ each may combine with a carbon atomattached thereto to form a saturated or unsaturated five- orsix-membered carbocyclic or heterocyclic group,

R⁷ is as defined in formula (a),

(2) a group of formula (a2):

wherein

R³ to R⁶ are as defined in formula (a1),

R¹¹ and R¹² are as defined in formula (a), and

(3) a group of formula (a3):

wherein

R^(3a) to R^(6a), which may be the same or different, represent

a hydrogen atom,

a halogen atom, or

C₁₋₆ alkyl, and

R¹³ and R¹⁴ are as defined in formula (a).

When A represents a group of formula (a1) and R³ and R⁴, R⁴ and R⁵, orR⁵ and R⁶ in formula (a1) form a carbocyclic or heterocyclic group, acyclic group may be formed at a position of any one of a combination ofR³ with R⁴, a combination of R⁴ with R⁵, or a combination of R⁵ with R⁶.Alternatively, a cyclic group may be formed at two or more positions ofR³ and R⁴, R⁴ and R⁵, and R⁵ and R⁶. In this case, A may combine withthe carbocyclic ring of formula (a1) to form a tricyclic group.

When A represents the group of formula (a1), R³, R⁴ and R⁶ in formula(a1), which may be the same or different, preferably represent

a hydrogen atom,

a halogen atom,

C₁₋₄ alkyl, or

C₁₋₄ alkoxy optionally substituted by a halogen atom or phenyl.

R⁵ in formula (a1) preferably represents

a hydrogen atom,

hydroxyl,

a halogen atom,

C₁₋₄ alkyl,

C₁₋₄ alkoxy optionally substituted by a halogen atom or phenyl,

C₂₋₄ alkenylcarbonyloxy,

C₁₋₂ alkylcarbonyl,

C₁₋₂ alkylthio, or

phenyl optionally substituted by a halogen atom.

In a more preferred embodiment of the present invention, R⁵ may berepresented by —OR⁷³ wherein R⁷³ represents a hydrogen atom, or C₁₋₄alkyl optionally substituted by phenyl.

In another preferred embodiment of the present invention, R⁵ is selectedfrom groups other than a hydrogen atom.

In one preferred embodiment of the present invention, at least one of R³to R⁶ in formula (a1) is selected from group other than a hydrogen atom.

In another one preferred embodiment of the present invention, R⁴combines with R⁵ to form phenyl as follows, and this phenyl combineswith phenyl in formula (a1) to form a bicyclic group.

wherein R⁷⁴ to R⁷⁷ represent a hydrogen atom, a halogen atom, hydroxyl,or C₁₋₄ alkyl, preferably a hydrogen atom.

In one preferred embodiment of the present invention, R⁷ in formula (a1)represents a hydrogen atom, C₁₋₄ alkyl, or phenyl in which the phenylgroup is optionally substituted by hydroxyl, C₁₋₄ alkyl, or C₁₋₄ alkoxy.More preferably, R⁷ represents a hydrogen atom, methyl, ethyl, orphenyl, and the phenyl group is optionally substituted by hydroxyl, C₁₋₄alkyl, or C₁₋₄ alkoxy. In this case, more preferably, R⁵ is selectedfrom groups other than a hydrogen atom.

In another preferred embodiment of the present invention, R⁷ in formula(a1) represents group —O—R⁸ or group —N(—R⁹)R¹⁰.

When R⁷ in formula (a1) represents group —O—R⁸, R⁸ preferably representsunsubstituted C₁₋₈ alkyl; C₁₋₄ alkyl substituted by phenyl; C₂₋₈alkenyl; or phenyl optionally substituted by a halogen atom. Morepreferably, R⁸ represents unsubstituted C₁₋₈ alkyl; methyl substitutedby phenyl; C₂₋₈ alkenyl; or phenyl. In this case, more preferably, R⁵ isselected from groups other than a hydrogen atom.

When R⁷ in formula (a1) represents group —N(—R⁹)R¹⁰, preferably, atleast one of R⁹ and R¹⁰ represents a hydrogen atom and the othersubstituent represents

a hydrogen atom,

C₁₋₆ alkyl,

a saturated or unsaturated five- or six-membered carbocyclic group inwhich the carbocyclic group is optionally substituted by a halogen atom,or

naphthyl optionally substituted by a halogen atom, or

R⁹ and R¹⁰ combine with a nitrogen atom attached thereto to form asaturated five- or six-membered heterocyclic group in which theheterocyclic group may further comprise at least one heteroatom. Morepreferably, at least one of R⁹ and R¹⁰ represents a hydrogen atom, and

the other substituent represents a hydrogen atom, C₁₋₄ alkyl, asaturated or unsaturated six-membered carbocyclic group in which thecarbocyclic group is optionally substituted by a halogen atom, ornaphthyl, or

R⁹ and R¹⁰ combine with a nitrogen atom attached thereto to form asaturated six-membered heterocyclic group in which the heterocyclicgroup may further comprise at least one heteroatom. In this case, morepreferably, R⁵ is selected from groups other than a hydrogen atom.

When A represents the group of formula (a2), preferably, R¹¹ and R¹² informula (a2) combine with a nitrogen atom attached thereto to form asaturated or unsaturated five- or six-membered heterocyclic group inwhich the heterocyclic group may further comprise one or moreheteroatoms and is optionally substituted by C₁₋₄ alkyl optionallysubstituted by hydroxyl; or a saturated five- or six-memberedheterocyclic group. In this case, preferably, R³, R⁴, and R⁶ in formula(a2) represent a hydrogen atom, hydroxyl, or a halogen atom, and R⁵ informula (a2) represents C₁₋₄ alkyl.

More preferably, R¹¹ and R¹² combine with a nitrogen atom attachedthereto to form a saturated five- or six-membered heterocyclic group inwhich the heterocyclic group may further comprise one or moreheteroatoms. Still more preferably, R¹¹ and R¹² combine with a nitrogenatom attached thereto to form piperidino, 2-piperidyl, or morpholino.

When A represents the group of formula (a3), preferably, R¹³ representsC₁₋₄ alkyl, more preferably methyl or ethyl, still more preferablymethyl.

R¹⁴ in formula (a3) preferably represents hydroxyl; C₁₋₄ alkoxyoptionally substituted by phenyl; C₂₋₆ alkenyloxy; phenyloxy; or aminooptionally substituted by a six-membered unsaturated heterocyclic group.In this case, more preferably, R¹³ represents methyl.

Preferably, R^(3a) and R^(6a) in formula (a3) represent a hydrogen atom,and R^(4a) and R^(5a) represent C₁₋₆ alkyl. More preferably, R^(3a) andR^(6a) represent a hydrogen atom, and R^(4a) and R^(5a) representmethyl.

In formula (I), the group of formula (b), which A may represent, ispreferably any group selected from the group consisting of formulae (b1)to (b3):

(4) a group of formula (b1):

wherein

R²⁵ to R²⁷, which may be the same or different, represent

a hydrogen atom,

a halogen atom,

C₁₋₆ alkyl,

C₁₋₈ alkoxy,

C₁₋₄ alkylcarbonyl,

C₁₋₄ alkylthio, or

phenylcarbonyl,

R²⁵ and R²⁶, and R²⁶ and R²⁷ each may combine with a carbon atomattached thereto to form a saturated or unsaturated five- orsix-membered carbocyclic or heterocyclic group,

R²⁸ represents

a hydrogen atom,

a halogen atom,

nitro,

cyano,

C₁₋₆ alkyl in which the alkyl group is optionally substituted byhydroxyl; phenyl; amino optionally substituted by C₁₋₄ alkyl; C₁₋₄alkylcarbonyloxy; or a saturated or unsaturated six-memberedheterocyclic group optionally substituted by C₁₋₄ alkyl,

C₁₋₈ alkoxy,

C₁₋₄ alkylcarbonyl,

C₂₋₆ alkenyl optionally substituted by a saturated or unsaturatedsix-membered carbocyclic group,

C₂₋₆ alkynyl optionally substituted by C₁₋₂ alkylsilyl,

a saturated or unsaturated three- to eight-membered carbocyclic oxygroup,

a saturated or unsaturated six-membered carbocyclic carbonyl orheterocyclic carbonyl group optionally substituted by C₁₋₄ alkyl, or

a saturated or unsaturated three- to eight-membered carbocyclic orheterocyclic group in which the carbocyclic or heterocyclic group isoptionally substituted by hydroxyl; cyano; a halogen atom; C₁₋₄ alkoxy;phenyloxy; C₁₋₄ alkylcarbonyl; amino optionally substituted by C₁₋₄alkyl or C₁₋₄ alkylcarbonyl; aminocarbonyl optionally substituted byC₁₋₄ alkyl; or C₁₋₄ alkyl optionally substituted by hydroxyl or ahalogen atom,

(5) a group of formula (b2):

wherein

R²⁹ to R³², which may be the same or different, represent

a hydrogen atom,

a halogen atom, or

C₁₋₆ alkyl optionally substituted by hydroxyl,

R²⁹ and R³⁰, and R³¹ and R³² each may combine with a carbon atomattached thereto to form a saturated or unsaturated five- orsix-membered carbocyclic or heterocyclic group in which the carbocyclicor heterocyclic group is optionally substituted by a halogen atom orC₁₋₄ alkyl, and

(6) a group of formula (b3):

wherein

R³³ to R³⁶, which may be the same or different, represent

a hydrogen atom,

a halogen atom, or

C₁₋₆ alkyl optionally substituted by hydroxyl,

R³³ and R³⁴, R³⁴ and R³⁵, and R³⁵ and R³⁶ each may combine with a carbonatom attached thereto to form a saturated or unsaturated five- orsix-membered carbocyclic or heterocyclic group in which the carbocyclicor heterocyclic group is optionally substituted by a halogen atom orC₁₋₄ alkyl.

When A represents the group of formula (b1), R²⁵ in formula (b1)preferably represents a hydrogen atom or a halogen atom, more preferablya hydrogen atom.

R²⁶ in formula (b1) preferably represents a hydrogen atom, a halogenatom, or C₁₋₄ alkyl, more preferably a hydrogen atom, a halogen atom,methyl, or ethyl.

R²⁷ in formula (b1) preferably represents a hydrogen atom, a halogenatom, C₁₋₄ alkyl, C₁₋₄ alkoxy, or C₁₋₄ alkylthio, more preferably ahalogen atom, methyl, ethyl, or methoxy.

In one more preferred embodiment of the present invention,

R²⁵ represents a hydrogen atom,

R²⁶ represents a hydrogen atom, a halogen atom, or C₁₋₄ alkyl, and

R²⁷ represents a hydrogen atom, a halogen atom, C₁₋₄ alkyl, C₁₋₄ alkoxy,or C₁₋₄ alkylthio.

In one still more preferred embodiment of the present invention, R²⁵represents a hydrogen atom, R²⁶ represents methyl, and R²⁷ representsmethyl.

In another preferred embodiment of the present invention, R²⁶ and R²⁷combine with a carbon atom attached thereto to form an unsaturatedsix-membered carbocyclic or heterocyclic group. In this case, formula(b1) may be represented by formula.

wherein R²⁵ is as defined above,

R⁷¹ represents methyl, ethyl, phenyl, or optionally substituted2-pyridyl,

R⁸⁶ to R⁸⁹ represent a hydrogen atom, a halogen atom, or C₁₋₄ alkyl,and, preferably, all of R⁸⁶ to R⁸⁹ represent a hydrogen atom, and

all of Es represent a carbon atom, or alternatively, any one of Esrepresents a nitrogen atom with the remaining Es representing a carbonatom.

In the above formula, preferably, all of Es represent a carbon atom, oralternatively, any of Es connected directly to R⁸⁶ or R⁸⁸ represents anitrogen atom with the remaining Es representing a carbon atom.

R²⁸ in formula (b1) preferably represents

a hydrogen atom,

a halogen atom,

nitro,

cyano,

C₁₋₆ alkyl in which the alkyl group is optionally substituted byhydroxyl; phenyl; amino optionally substituted by C₁₋₄ alkyl; C₁₋₄alkylcarbonyloxy; or a saturated or unsaturated six-memberedheterocyclic group optionally substituted by C₁₋₄ alkyl,

C₁₋₄ alkoxy,

C₁₋₄ alkylcarbonyl,

C₂₋₆ alkenyl optionally substituted by phenyl,

C₂₋₆ alkynyl optionally substituted by C₁₋₂ alkylsilyl,

a saturated or unsaturated three- to eight-membered carbocyclic oxygroup,

an unsaturated six-membered heterocyclic carbonyl group optionallysubstituted by C₁₋₄ alkyl,

phenylcarbonyl, or

a saturated or unsaturated three- to eight-membered carbocyclic orheterocyclic group in which the carbocyclic or heterocyclic group isoptionally substituted by hydroxyl; cyano; a halogen atom; C₁₋₄ alkoxy;phenyloxy; C₁₋₄ alkylcarbonyl; amino optionally substituted by C₁₋₄alkyl or C₁₋₄ alkylcarbonyl; aminocarbonyl optionally substituted byC₁₋₄ alkyl; or C₁₋₄ alkyl optionally substituted by hydroxyl or ahalogen atom.

Here when R²⁸ represents alkylcarbonyl, carbocyclic carbonyl, orheterocyclic carbonyl group, R²⁸ may be represented by —C(═O)R⁷¹. Inthis case, R⁷¹ represents methyl, ethyl, phenyl, or optionallysubstituted 2-pyridyl.

When R²⁸ represents alkyl substituted by alkylcarbonyloxy, R²⁸ may berepresented by —C(—R⁷¹)OR⁷² wherein R⁷¹ is as defined above and R⁷²represents a hydrogen atom or methylcarbonyl.

When R²⁸ represents a carbocyclic oxy group, R²⁸ may be represented by—OR⁸⁰ wherein R⁸⁰ preferably represents cyclopentyl, cyclohexyl, orphenyl.

When R²⁸ represents alkyl substituted by amino, R²⁸ may be representedby —CH₂—N(—R⁸⁴)R⁸⁵ wherein R⁸⁴ and R⁸⁵ represent C₁₋₄ alkyl, preferablymethyl, ethyl, propyl, i-propyl, butyl, t-butyl, or i-butyl.

In a more preferred embodiment of the present invention, R²⁸ representsa saturated or unsaturated three- to eight-membered carbocyclic orheterocyclic group in which the carbocyclic or heterocyclic group isoptionally substituted by hydroxyl; cyano; a halogen atom; C₁₋₄ alkoxy;phenyloxy; C₁₋₄ alkylcarbonyl; amino optionally substituted by C₁₋₄alkyl or C₁₋₄ alkylcarbonyl; aminocarbonyl optionally substituted byC₁₋₄ alkyl; or C₁₋₄ alkyl optionally substituted by hydroxyl or ahalogen atom.

In a more preferred embodiment of the present invention, R²⁸ representsa saturated or unsaturated four- to seven-membered carbocyclic orheterocyclic group, still more preferably a saturated or unsaturatedfive- or six-membered carbocyclic or heterocyclic group, particularlypreferably pyridyl, furyl, thienyl, pyrrolyl, pyridazyl, pyrimidyl,isoxazolyl, isothiazolyl, thiazolyl, or pyrazyl. These rings areoptionally substituted.

In another one more preferred embodiment of the present invention,

R²⁵ represents a hydrogen atom,

R²⁶ represents a hydrogen atom, a halogen atom, or C₁₋₄ alkyl,

R²⁷ represents a hydrogen atom, a halogen atom, C₁₋₄ alkyl, C₁₋₄ alkoxy,or C₁₋₄ alkylthio,

R²⁶ and R²⁷ may combine with a carbon atom attached thereto to form anunsaturated six-membered carbocyclic or heterocyclic group, and, morepreferably, in this case,

R²⁸ represents a saturated or unsaturated four- to seven-memberedcarbocyclic or heterocyclic group in which the carbocyclic orheterocyclic group is optionally substituted by hydroxyl; cyano; ahalogen atom; C₁₋₄ alkoxy; phenyloxy; C₁₋₄ alkylcarbonyl; aminooptionally substituted by C₁₋₄ alkyl or C₁₋₄ alkylcarbonyl;aminocarbonyl optionally substituted by C₁₋₄ alkyl; or C₁₋₄ alkyloptionally substituted by hydroxyl or a halogen atom.

When A represents the group of formula (b2), R²⁹ in formula (b2)preferably represents a hydrogen atom. R³⁰ in formula (b2) preferablyrepresents a hydrogen atom or C₁₋₄ alkyl.

R³¹ and R³² in formula (b2) preferably combine with carbon atom attachedthereto to from an unsaturated five- or six-membered carbocyclic orheterocyclic group in which the carbocyclic or heterocyclic group isoptionally substituted by a halogen atom or C₁₋₄ alkyl. More preferably,R³¹ combines with R³² to form a phenyl ring or a thienyl ring.

When A represents the group of formula (b3), R³³ and R³⁴ in formula (b3)preferably represent a hydrogen atom, a halogen atom, methyl, or ethyl,more preferably a hydrogen atom.

R³⁵ and R³⁶ in formula (b3) combine with a carbon atom attached theretoto preferably form an unsaturated five- or six-membered carbocyclic orheterocyclic group, more preferably phenyl.

When A represents the group of formula (c), at least one of R²⁰ and R²⁴in formula (c) is preferably selected from a group other than a hydrogenatom.

In formula (c), preferably, R²¹ and R²² or R²² and R²³ combine with acarbon atom attached thereto to form a saturated or unsaturated five- orsix-membered carbocyclic or heterocyclic group. The carbocyclic orheterocyclic group is optionally substituted by a halogen atom, C₁₋₄alkyl, C₁₋₄ alkylcarbonyl, C₁₋₆ alkoxycarbonyl, or an oxygen atom andmay condense with another saturated or unsaturated five- or six-memberedcarbocyclic or heterocyclic group to form, together with thesix-membered carbocyclic ring in formula (c), a tricyclic group. In thiscase, preferably, any one of or both R²⁰ and R²⁴ is selected from groupsother than a hydrogen atom.

In another preferred embodiment of the present invention, R²² represents

C₁₋₁₀ alkyl optionally substituted by hydroxyl or a saturated orunsaturated six-membered carbocyclic or heterocyclic group,

C₁₋₈ alkoxy,

amino optionally substituted by phenyl,

nitro, or

a saturated or unsaturated five- or six-membered carbocyclic orheterocyclic group in which the carbocyclic or heterocyclic group isoptionally substituted by C₁₋₆ alkyl. In this case, any one of or bothR²⁰ and R²⁴ is selected from groups other than a hydrogen atom.

When R²⁰ or R²⁴ is optionally substituted C₂₋₆ alkenyl, preferably, R²⁰or R²⁴ may be represented by —C═C(R⁶¹)(R⁶²) wherein R⁶¹ and R⁶², whichmay be the same or different, represent a hydrogen atom, C₁₋₄ alkyl,C₁₋₄ alkoxy, C₁₋₄ alkoxycarbonyl, or phenyl. More preferably, R⁶¹ andR⁶² represent a hydrogen atom, C₁₋₂ alkoxycarbonyl, or phenyl.

When R²⁰ or R²⁴ is amino optionally substituted by phenyl, preferably,R²⁰ or R²⁴ is represented by formula

wherein

R⁶³ to R⁶⁷, which may be the same or different, represent a hydrogenatom, hydroxyl, a halogen atom, or C₁₋₄ alkyl.

When R²¹ and R²², or R²² and R²³ combine with a carbon atom attachedthereto to form a carbocyclic or heterocyclic group, the formed ringcombines with the carbocyclic ring of formula (c) to form a bicyclicgroup. Examples of such bicyclic groups include groups such as naphthyl,indole, benzimidazole, quinoline, isoquinoline, and quinazoline.

For example, when the bicyclic group is in the form of an indole ring,formula (c) may be represented by formula

wherein

R²⁰ and R²⁴ are as defined above,

R⁶⁸ to R⁷⁰, which may be the same or different, represent a hydrogenatom, a halogen atom, C₁₋₂ alkylcarbonyl, C₁₋₂ alkoxycarbonyl, or C₁₋₄alkyl, and, preferably, R⁶⁹ represents a hydrogen atom.

When the bicyclic group is in the form of an isoquinoline ring, formula(c) may be represented by formula

wherein

R²⁰, R²³ and R²⁴ are as defined above,

R⁹⁰ to R⁹², which may be the same or different, represent a hydrogenatom, a halogen atom, C₁₋₂ alkylcarbonyl, C₁₋₂ alkoxycarbonyl, or C₁₋₄alkyl.

When the bicyclic group is in the form of a quinazoline ring, formula(c) may be represented by formula

wherein

R²⁰, R²³ and R²⁴ are as defined above,

R⁹³ represents a hydrogen atom, a halogen atom, C₁₋₂ alkylcarbonyl, C₁₋₂alkoxycarbonyl, or C₁₋₄ alkyl, and, preferably, R⁹³ represents ahydrogen atom.

In a preferred embodiment of the present invention, A is selected fromthe group of formula (a) and the group of formula (b).

In one preferred embodiment of the present invention, when one of R¹ andR² is selected from C₁₋₆ alkyl with the other substituent being selectedfrom the group consisting of a hydrogen atom, benzyl, and groups offormulae (i), (ii-a), (iii-a), (iv-a), (v), and (vi), A is selected fromthe group of formula (a1) or the group of formula (b1). In this case,preferably, X represents CH and Z represents —O—.

When A represents the group of formula (a1) and R⁷ represents a hydrogenatom, C₁₋₄ alkyl, or phenyl in which the phenyl group is optionallysubstituted by hydroxyl, C₁₋₄ alkyl, or C₁₋₄ alkoxy, preferably, Xrepresents CH or N and Z represents —O—.

When A represents the group of formula (a1) with R⁷ representing group—O—R⁸, preferably, X represents CH and Z represents —O—, —S—, or—C(═O)—.

When A represents the group of formula (a1) with R⁷ representing group—N(—R⁹)R¹⁰, preferably, X represents CH and Z represents —O—.

When A represents the group of formula (a2) or formula (a3) with both R¹and R² being selected from C₁₋₆ alkyl, preferably, X represents CH and Zrepresents —O—.

When A represents the group of formula (b1) with both R¹ and R² beingselected from C₁₋₆ alkyl, preferably, X represents CH and Z represents—O— or —NH—.

When A represents the group of formula (b2) with both R¹ and R² beingselected from C₁₋₆ alkyl, preferably, X represents CH and Z represents—O—.

When A represents the group of formula (b3) with both R¹ and R² beingselected from C₁₋₆ alkyl, preferably, X represents CH and Z represents—O— or —S—.

When A represents the group of formula (c), preferably, R¹ and R², whichmay be the same or different, are selected from C₁₋₆ alkyl. In thiscase, preferably, X represents CH and Z represents —O—.

In a preferred embodiment of the present invention,

when X represents CH and Z represents —O—, A is selected from the groupsof formulae (a) to (c),

when X represents CH and Z represents —NH—, A represents the group offormula (a3),

when X represents CH and Z represents —C(═O)—, A represents the group offormula (a1),

when X represents CH and Z represents —S—, A represents the group offormula (a1) or formula (b3), or

when X represents N and Z represents —O—, A represents the group offormula (a1) or formula (b1).

In one preferred embodiment of the present invention, the compoundrepresented by formula (I) may be a compound represented by formula(100):

wherein

X represents CH or N,

Z represents —O—, —NH—, —S—, or —C(═O)—,

R¹⁰¹ and R¹⁰², which may be the same or different, represent any groupselected from the group consisting of

a hydrogen atom,

C₁₋₆ alkyl,

benzyl, and

groups of formulae (i), (ii-a), (iii-a), (iv-a), (v), and (vi),

R¹⁰³, R¹⁰⁴ and R¹⁰⁶, which may be the same or different, represent

a hydrogen atom,

a halogen atom,

C₁₋₆ alkyl,

C₁₋₁₀ alkoxy optionally substituted by a halogen atom or phenyl,

C₂₋₆ alkenylcarbonyloxy,

C₁₋₄ alkylcarbonyl, or

phenyl optionally substituted by a halogen atom,

R¹⁰⁵ represents

hydroxyl,

a halogen atom,

C₁₋₆ alkyl,

C₁₋₁₀ alkoxy optionally substituted by a halogen atom or phenyl,

C₂₋₆ alkenylcarbonyloxy,

C₁₋₄ alkylcarbonyl,

C₁₋₄ alkylthio, or

phenyl optionally substituted by a halogen atom,

R¹⁰³ and R¹⁰⁴, R¹⁰⁴ and R¹⁰⁵, and R¹⁰⁵ and R¹⁰⁶ each may combine with acarbon atom attached thereto to form a saturated or unsaturated five- orsix-membered carbocyclic or heterocyclic group,

R¹⁰⁷ represents

a hydrogen atom,

C₁₋₄ alkyl, or

phenyl optionally substituted by hydroxyl, C₁₋₄ alkyl, or C₁₋₄ alkoxy.

In one more preferred embodiment of the present invention, in formula(100),

at least one of R¹⁰¹ and R¹⁰² represents methyl, and

R¹⁰⁷ represents a hydrogen atom, methyl, ethyl, or phenyl optionallysubstituted by hydroxyl, C₁₋₄ alkyl or C₁₋₄ alkoxy. In this case,preferably, Z represents —O—.

Specific examples of compounds represented by formula (100) includecompounds 26 to 76, 118 to 162, 172 to 192, 200, and 312 to 321.

In one preferred embodiment of the present invention, the compoundrepresented by formula (I) may be a compound represented by formula(200):

wherein

X represents CH or N,

Z represents —O—, —NH—, —S—, or —C(═O)—,

R²⁰¹ and R²⁰², which may be the same or different, represent any groupselected from the group consisting of

a hydrogen atom,

C₁₋₆ alkyl,

benzyl, and

groups of formulae (i), (ii-a), (iii-a), (iv-a), (v), and (vi),

R²⁰³ to R²⁰⁶, which may be the same or different, represent

a hydrogen atom,

hydroxyl,

a halogen atom,

C₁₋₆ alkyl,

C₁₋₁₀ alkoxy optionally substituted by a halogen atom or phenyl,

C₂₋₆ alkenylcarbonyloxy,

C₁₋₄ alkylcarbonyl,

C₁₋₄ alkylthio, or

phenyl optionally substituted by a halogen atom,

R²⁰³ and R²⁰⁴, R²⁰⁴ and R²⁰⁵, and R²⁰⁵ and R²⁰⁶ each may combine with acarbon atom attached thereto to form a saturated or unsaturated five- orsix-membered carbocyclic or heterocyclic group,

provided that at least one of R²⁰³ to R²⁰⁶ is selected from a groupother than a hydrogen atom, and

R²⁰⁸ represents unsubstituted C₁₋₈ alkyl; C₁₋₄ alkyl substituted byphenyl; C₂₋₈ alkenyl; or phenyl optionally substituted by a halogenatom.

In one more preferred embodiment of the present invention, in formula(200),

R²⁰⁸ represents unsubstituted C₁₋₈ alkyl; methyl substituted by phenyl;C₂₋₈ alkenyl; or phenyl. In this case, preferably, Z represents —O—, S—,or —C(═O)—.

Specific examples of compounds represented by formula (200) includecompounds 79 to 103, 163, 201, 322 to 327, and 419.

In one preferred embodiment of the present invention, the compoundsrepresented by formula (I) may be compounds represented by formula(300):

wherein

X represents CH or N,

Z represents —O—, —NH—, —S—, or —C(═O)—,

R³⁰¹ and R³⁰², which may be the same or different, represent any groupselected from the group consisting of

a hydrogen atom,

C₁₋₆ alkyl,

benzyl, and

groups of formulae (i), (ii-a), (iii-a), (iv-a), (v), and (vi),

R³⁰³ to R³⁰⁶, which may be the same or different, represent

a hydrogen atom,

hydroxyl,

a halogen atom,

C₁₋₆ alkyl,

C₁₋₁₀-alkoxy optionally substituted by a halogen atom or phenyl,

C₂₋₆ alkenylcarbonyloxy,

C₁₋₄ alkylcarbonyl,

C₁₋₄ alkylthio, or

phenyl optionally substituted by a halogen atom,

R³⁰³ and R³⁰⁴, R³⁰⁴ and R³⁰⁵, and R³⁰⁵ and R³⁰⁶ each may combine with acarbon atom attached thereto to form a saturated or unsaturated five- orsix-membered carbocyclic or heterocyclic group,

provided that at least one of R³⁰³ to R³⁰⁶ is selected from a groupother than a hydrogen atom, and

at least one of R³⁰⁹ and R³¹⁰ represents a hydrogen atom and the othersubstituent represents

a hydrogen atom,

C₁₋₆ alkyl,

a saturated or unsaturated five- or six-membered carbocyclic group inwhich the carbocyclic group is optionally substituted by a halogen atom,or

naphthyl optionally substituted by a halogen atom, or

R³⁰⁹ and R³¹⁰ combine with a nitrogen atom attached thereto to form asaturated five- or six-membered heterocyclic group which may furthercomprise one or more heteroatoms.

In one more preferred embodiment of the present invention, in formula(300),

at least one of R³⁰⁹ and R³¹⁰ represents a hydrogen atom and

the other substituent represents a hydrogen atom, C₁₋₄ alkyl, asaturated or unsaturated six-membered carbocyclic group in which thecarbocyclic group is optionally substituted by a halogen atom, ornaphthyl, or

R³⁰⁹ and R³¹⁰ combine with a nitrogen atom attached thereto to form asaturated six-membered heterocyclic group which may further comprise oneor more heteroatoms. In this case, preferably, Z represents —O—.

Specific examples of compounds represented by formula (300) includecompounds 104 to 114.

In one preferred embodiment of the present invention, the compoundrepresented by formula (I) may be a compound represented by formula(400):

wherein

X represents CH or N,

Z represents —O—, —NH—, —S—, or —C(═O)—,

R⁴⁰¹ and R⁴⁰², which may be the same or different, represent any groupselected from C₁₋₆ alkyl,

R⁴⁰³, R⁴⁰⁴, and R⁴⁰⁶ represent a hydrogen atom, hydroxyl, or a halogenatom,

R⁴⁰⁵ represents C₁₋₄ alkyl,

R⁴¹¹ and R⁴¹² combine with a nitrogen atom attached thereto to form asaturated or unsaturated five- or six-membered heterocyclic group inwhich the heterocyclic group may further comprise one or moreheteroatoms and is optionally substituted by C₁₋₄ alkyl optionallysubstituted by hydroxyl; or a saturated five- or six-memberedheterocyclic group.

In one more preferred embodiment of the present invention, in formula(400),

R⁴⁰¹ and R⁴⁰² represent methyl,

R⁴¹¹ and R⁴¹² combine with a nitrogen atom attached thereto to form asaturated five- or six-membered heterocyclic group in which theheterocyclic group may further comprise one or more heteroatoms. In thiscase, preferably, Z represents —O—.

Specific examples of compounds represented by formula (400) includecompound 6.

In one preferred embodiment of the present invention, the compoundrepresented by formula (I) may be a compound represented by formula(500):

wherein

X represents CH or N,

Z represents —O—, —NH—, —S—, or —C(═O)—,

R⁵⁰¹ and R⁵⁰², which may be the same or different, represent any groupselected from C₁₋₆ alkyl,

R⁵⁰³ and R⁵⁰⁶ represent a hydrogen atom,

R⁵⁰⁴ and R⁵⁰⁵ represent C₁₋₆ alkyl,

R⁵¹³ represents C₁₋₄ alkyl, and

R⁵¹⁴ represents hydroxyl; C₁₋₄ alkoxy optionally substituted by phenyl;C₂₋₆ alkenyloxy; phenyloxy; or amino optionally substituted by asix-membered unsaturated heterocyclic group.

In one more preferred embodiment of the present invention, in formula(500),

R⁵⁰¹ and R⁵⁰² represent methyl,

R⁵⁰³ and R⁵⁰⁶ represent a hydrogen atom,

R⁵⁰⁴ and R⁵⁰⁵ represent methyl, and

R⁵¹³ represents methyl. In this case, preferably, Z represents —O—.

Specific examples of compounds represented by formula (500) includecompounds 193 to 199.

In one preferred embodiment of the present invention, the compoundrepresented by formula (I) may be a compound represented by formula(600):

wherein

X represents CH or N,

Z represents —O—, —NH—, —S—, or —C(═O)—,

R⁶⁰¹ and R⁶⁰², which may be the same or different, represent any groupselected from the group consisting of

a hydrogen atom,

C₁₋₆ alkyl,

benzyl, and

groups of formulae (i), (ii-a), (iii-a), (iv-a), (v), and (vi),

R⁶²⁵ represents a hydrogen atom,

R⁶²⁶ represents a hydrogen atom, a halogen atom, or C₁₋₄ alkyl,

R⁶²⁷ represents a hydrogen atom, a halogen atom, C₁₋₄ alkyl, C₁₋₄alkoxy, or C₁₋₄ alkylthio,

R⁶²⁶ and R⁶²⁷ may combine with a carbon atom attached thereto to form anunsaturated six-membered carbocyclic or heterocyclic group,

R⁶²⁸ represents

a hydrogen atom,

a halogen atom,

nitro,

cyano,

C₁₋₆ alkyl in which the alkyl group is optionally substituted byhydroxyl; phenyl; amino optionally substituted by C₁₋₄ alkyl; C₁₋₄alkylcarbonyloxy; or a saturated or unsaturated six-memberedheterocyclic group optionally substituted by C₁₋₄ alkyl,

C₁₋₈ alkoxy,

C₁₋₄ alkylcarbonyl,

C₂₋₆ alkenyl optionally substituted by a saturated or unsaturatedsix-membered carbocyclic group,

C₂₋₆ alkynyl optionally substituted by C₁₋₂ alkylsilyl,

a saturated or unsaturated three- to eight-membered carbocyclic oxygroup,

a saturated or unsaturated six-membered carbocyclic carbonyl orheterocyclic carbonyl group optionally substituted by C₁₋₄ alkyl, or

a saturated or unsaturated three- to eight-membered carbocyclic orheterocyclic group in which the carbocyclic or heterocyclic group isoptionally substituted by hydroxyl; cyano; a halogen atom; C₁₋₄ alkoxy;phenyloxy; C₁₋₄ alkylcarbonyl; amino optionally substituted by C₁₋₄alkyl or C₁₋₄ alkylcarbonyl; aminocarbonyl optionally substituted byC₁₋₄ alkyl; or C₁₋₄ alkyl optionally substituted by hydroxyl or ahalogen atom.

In one more preferred embodiment of the present invention, in formula(600),

R⁶²⁸ represents a saturated or unsaturated four- to seven-memberedcarbocyclic or heterocyclic group in which the carbocyclic orheterocyclic group is optionally substituted by hydroxyl; cyano; ahalogen atom; C₁₋₄ alkoxy; phenyloxy; C₁₋₄ alkylcarbonyl; aminooptionally substituted by C₁₋₄ alkyl or C₁₋₄ alkylcarbonyl;aminocarbonyl optionally substituted by C₁₋₄ alkyl; or C₁₋₄ alkyloptionally substituted by hydroxyl or a halogen atom. In this case,preferably, Z represents —O— or —NH—.

Specific examples of compounds represented by formula (600) includecompounds 115 to 117, 202 to 292, 310, 311, 328 to 409, 415 to 418, 421to 424, and 426 to 469.

In one preferred embodiment of the present invention, the compoundrepresented by formula (I) may be a compound represented by formula(700):

wherein

X represents CH or N,

Z represents —O—, —NH—, —S—, or —C(═O)—,

R⁷⁰¹ and R⁷⁰², which may be the same or different, represent any groupselected from C₁₋₆ alkyl,

R⁷²⁹ represents a hydrogen atom,

R⁷³⁰ represents a hydrogen atom or C₁₋₄ alkyl, and

R⁷³¹ and R⁷³² combine with a carbon atom attached thereto to form anunsaturated five- or six-membered carbocyclic or heterocyclic group inwhich the carbocyclic or heterocyclic group is optionally substituted bya halogen atom or C₁₋₄ alkyl.

In one more preferred embodiment of the present invention, in formula(700),

R⁷⁰¹ and R⁷⁰² represent methyl. In this case, preferably, Z represents—O—.

Specific examples of compounds represented by formula (700) includecompounds 307 to 309.

In one preferred embodiment of the present invention, the compoundrepresented by formula (I) may be a compound represented by formula(800):

wherein

X represents CH or N,

Z represents —O—, —NH—, —S—, or —C(═O)—,

R⁸⁰¹ and R⁸⁰², which may be the same or different, represent any groupselected from C₁₋₆ alkyl,

R⁸³³ and R⁸³⁴ represent a hydrogen atom, and

R⁸³⁵ and R⁸³⁶ combine with a carbon atom attached thereto to form anunsaturated five- or six-membered carbocyclic or heterocyclic group.

In one more preferred embodiment of the present invention, in formula(800),

Z represents —O— or —S—,

R⁸⁰¹ and R⁸⁰² represent methyl,

R⁸³⁵ and R⁸³⁶ combine with a carbon atom attached thereto to formphenyl.

Specific examples of compounds represented by formula (800) includecompound 420.

In one preferred embodiment of the present invention, the compoundrepresented by formula (I) may be a compound represented by formula(900):

wherein

X represents CH or N,

Z represents —O—, —NH—, —S—, or —C(═O)—,

R⁹⁰¹ and R⁹⁰², which may be the same or different, represent any groupselected from C₁₋₆ alkyl,

R⁹²⁰, R⁹²¹, R⁹²³, and R⁹²⁴, which may be the same or different,represent

a hydrogen atom,

a halogen atom,

C₁₋₁₀ alkyl optionally substituted by hydroxyl, a saturated orunsaturated five- or six-membered carbocyclic or heterocyclic group,

C₁₋₈ alkoxy,

C₂₋₆ alkenyl optionally substituted by C₁₋₄ alkyl, C₁₋₄ alkoxy, anoxygen atom or phenyl,

phenylcarbonyl optionally substituted by C₁₋₄ alkyl,

amino optionally substituted by phenyl,

nitro, or

a saturated or unsaturated five- or six-membered carbocyclic orheterocyclic group in which the carbocyclic or heterocyclic group isoptionally substituted by C₁₋₆ alkyl,

provided that at least one of R⁹²⁰ and R⁹²⁴ is selected from a groupother than a hydrogen atom,

R⁹²² represents

C₁₋₁₀ alkyl optionally substituted by hydroxyl, a saturated orunsaturated six-membered carbocyclic or heterocyclic group,

C₁₋₈ alkoxy,

amino optionally substituted by phenyl,

nitro, or

a saturated or unsaturated five- or six-membered carbocyclic orheterocyclic group in which the carbocyclic or heterocyclic group isoptionally substituted by C₁₋₆ alkyl, and

R⁹²¹ and R⁹²², or R⁹²² and R⁹²³ may combine with a carbon atom attachedthereto to form a saturated or unsaturated five- or six-memberedcarbocyclic or heterocyclic group in which the carbocyclic orheterocyclic group is optionally substituted by a halogen atom, C₁₋₄alkyl, C₁₋₄ alkylcarbonyl, C₁₋₆ alkoxycarbonyl, or an oxygen atom, andthe carbocyclic or heterocyclic group may condense with anothersaturated or unsaturated five- or six-membered carbocyclic orheterocyclic group to form a tricyclic group together with thesix-membered carbocyclic ring of formula (c).

In one more preferred embodiment of the present invention, in formula(900),

at least one of R⁹²⁰ and R⁹²⁴ is selected from a group other than ahydrogen atom, and

R⁹²¹ and R⁹²², or R⁹²² and R⁹²³ combine with a carbon atom attachedthereto to form a saturated or unsaturated five- or six-memberedcarbocyclic or heterocyclic group in which the carbocyclic orheterocyclic group is optionally substituted by a halogen atom, C₁₋₄alkyl, C₁₋₄ alkylcarbonyl, C₁₋₆ alkoxycarbonyl, or an oxygen atom. Inthis case, preferably, Z represents —O—.

Specific examples of compounds represented by formula (900) includecompounds 1 to 5, 7 to 24, 77, 78, 164 to 171, 293 to 306, and 425.

Examples of preferred compounds according to the present inventioninclude compounds described in the working examples.

More preferred compounds according to the present invention includecompounds 195, 207, 260, 261, 270 to 274, 276, 278, 303, 305, 310, 311,339, 346, 369, 384 to 387, 392, 395, 396, 400, 411, 421, 422, 431, 436,437, 440, 441, 451, 459, 461, and 469 described in the working examples.

Salts or Solvates of Compounds

The compounds according to the present invention may formpharmaceutically acceptable salts thereof. Preferred examples of suchsalts include: alkali metal or alkaline earth metal salts such as sodiumsalts, potassium salts or calcium salts; hydrohalogenic acid salts suchas hydrofluoride salts, hydrochloride salts, hydrobromide salts, orhydroiodide salts; inorganic acid salts such as nitric acid salts,perchloric acid salts, sulfuric acid salts, or phosphoric acid salts;lower alkylsulfonic acid salts such as methanesulfonic acid salts,trifluoromethanesulfonic acid salts, or ethanesulfonic acid salts;arylsulfonic acid salts such as benzenesulfonic acid salts orp-toluenesulfonic acid salts; organic acid salts such as fumaric acidsalts, succinic acid salts, citric acid salts, tartaric acid salts,oxalic acid salts, maleic acid salts, acetic acid salts, malic acidsalts, lactic acid salts, or ascorbic acid salts; and amino acid saltssuch as glycine salts, phenylalanine salts, glutamic acid salts, oraspartic acid salts.

The compounds according to the present invention may form solvates. Suchsolvates include, for example, hydrates, alcoholates, for example,methanolates and ethanolates, and etherates, for example, diethyletherate.

Production of Compounds of Formula (I)

Compounds according to the present invention may be produced, forexample, according to schemes 1 to 34. Starting compounds necessary forthe synthesis of the compounds according to the present invention arecommercially available or alternatively may be easily produced byconventional methods.

In the following scheme, quinolone derivatives as an intermediate may besynthesized, for example, according to WO 97/17329.

4-Chloroquinoline derivatives may be synthesized by a conventionalmethod as described, for example, in Org. Synth. Col. Vol. 3, 272(1955), Acta Chim. Hung., 112, 241 (1983) or WO 98/47873.

4-Chloroquinazoline derivatives may be synthesized by a conventionalmethod as described in J. Am. Chem. Soc., 68, 1299 (1946), J. Am. Chem.Soc., 68, 1305 (1946), and Dai Yuuki Kagaku (Great Organic Chemistry),supervised by Kotake, Vol. 17, p 150, Asakura Publishing Co., Ltd.(published in 1967).

1 and 2) The compound, which is represented by formula (I) and in whichformula (I) is represented by formula (II) and A represents a group offormula (c), may be produced, for example, according to scheme 1 andscheme 2 below.

wherein each substituent is as defined above.

The contemplated 4-phenoxyquinoline derivative, 4-anilinoquinolinederivative, or corresponding quinazoline derivative may be synthesizedby reacting a phenol derivative or a corresponding aniline derivativewith a 4-chloroquinoline derivative or a corresponding quinazolinederivative in a suitable solvent, for example, o-dichlorobenzene, or inthe absence of a solvent, for example, at 120 to 180° C. In scheme 1,phosphoryl chloride may be used as the chlorinating agent.

3) The compound, which is represented by formula (I) and in whichformula (I) is represented by formula (II) and A represents a group offormulae (a1), (b1) to (b3), and (c), particularly a compound having asubstituent of a ketone at the o-position of A, may be produced, forexample, according to scheme 3 below.

wherein X′ represents a halogen atom; and each other substituent is asdefined above.

In this scheme, the contemplated compound of formula (I) may besynthesized by any one of the following three routes (i) to (iii).

(i) The contemplated compound of formula (I) may be synthesized byreacting a 4-chloroquinoline derivative or a corresponding quinazolinederivative with a phenol derivative or a corresponding anilinederivative in a suitable solvent, for example, o-dichlorobenzene, or inthe absence of a solvent, for example, at 120 to 180° C. (step (1)above).

(ii) The contemplated compound of formula (I) may be synthesized byreacting a 4-chloroquinoline derivative or a corresponding quinazolinederivative with an o-bromophenol derivative or a correspondingo-bromoaniline derivative in a suitable solvent, for example,o-dichlorobenzene, or in the absence of a solvent, for example, at 120to 180° C. (step (2) above), then subjecting the production products atits bromo site to dipole inversion using a metal base, for example,n-butyllithium, and reacting the produced anion with an acid chloride(step (3) above).

(iii) The contemplated compound of formula (I) may be produced byreacting a 4-chloroquinoline derivative or a corresponding quinazolinederivative with an O-hydroxybenzaldehyde derivative or a correspondingo-aminobenzaldehyde derivative in a suitable solvent, for example,o-dichlorobenzene, or in the absence of a solvent, for example, at 120to 180° C. (step (4) above), then reacting the reaction product with analkylating agent, for example, methylmagnesium bromide (step (5) above),and oxidizing the resultant alcohol (step (6) above).

4) The compound, which is represented by formula (I) and in whichformula (I) is represented by formula (II) and A represents a group offormula (a1) (particularly an amide compound), may be produced, forexample, according to scheme 4 below.

wherein each substituent is as defined above.

The ester-type compound of formula (I) may be produced by reacting a4-chloroquinoline derivative or a corresponding quinazoline derivativewith an o-hydroxybenzoic ester derivative or a correspondingo-aminobenzoic ester derivative in a suitable solvent, for example,o-dichlorobenzene, or in the absence of a solvent, for example, at 120to 180° C. (step (1) above). Next, the contemplated compound of formula(I) may be synthesized by hydrolyzing the ester-type compound with analkali (step (2) above) and reacting the hydrolyzation product with anamine using a condensing agent, for example,1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (step (3)above).

5) The compound, which is represented by formula (I) and in whichformula (I) is represented by formula (II) and a desired substituent ispresent at the 7-position of the quinoline or quinazoline ring in thecompound, may be produced, for example, according to scheme 5 below.

wherein each substituent is as defined above.

The contemplated compound of formula (I) may be synthesized by providinga 7-benzyloxy-4-chloroquinoline derivative or a correspondingquinazoline derivative, reacting the derivative with a phenol derivativeor a corresponding aniline derivative in a suitable solvent, forexample, o-dichlorobenzene, or in the absence of a solvent, for example,at 120 to 180° C. (step (1) above), then deprotecting a benzyl group inthe intermediate 5-1 thus obtained with an acid (step (2) above), andreacting the intermediate 5-2 thus obtained with an alkylating agent,for example, 1-bromo-2-chloroethane, in the presence of a base (step (3)above).

6) The compound, which is represented by formula (I) and in whichformula (I) is represented by formula (II) and Z represents —C(═O)—, maybe produced, for example, according to scheme 6 below.

wherein each substituent is as defined above.

The contemplated compound of formula (I) may be produced by reacting a4-quinolone derivative or a corresponding quinazolone derivative with abrominating agent, for example, phosphoryl bromide (step (1) above) andthen subjecting the reaction product at its bromo site to dipoleinversion using a metal base, for example, n-butyllithium, and reactingthe resultant anion with an acid chloride (step (2) above).

7) The compound, which is represented by formula (I) and in whichformula (I) is represented by formula (II) and in which A represents agroup of formula (c) and R²⁴ represents optionally substituted alkenyl,may be produced, for example, according to scheme 7 below.

wherein each substituent is as defined above.

The contemplated compound of formula (I) may be synthesized by reactinga 4-chloroquinoline derivative or a corresponding quinazoline derivativewith an o-hydroxybenzaldehyde derivative or a correspondingo-aminobenzaldehyde derivative in a suitable solvent, for example,o-dichlorobenzene, or in the absence of a solvent, for example, at 120to 180° C. (step (1) above) and then reacting the reaction product witha Witting reagent or a Horner-Emmons reagent, for example, phosphorusylide (step (2) above).

8) The compound, which is represented by formula (I) and in whichformula (I) is represented by formula (II) and A represents a group offormula (a2), may be produced, for example, according to scheme 8 below.

wherein each substituent is as defined above.

The contemplated compound of formula (I) may be synthesized by reactinga 4-chloroquinoline derivative or a corresponding quinazoline derivativewith an o-hydroxybenzaldehyde derivative or a correspondingo-aminobenzaldehyde derivative in a suitable solvent, for example,o-dichlorobenzene, or in the absence of a solvent, for example, at 120to 180° C. (step (1) above) and then reacting the reaction product withan amine (R¹¹R¹²NH) to give an imine which is then reduced (step (2)above).

9) The compound, which is represented by formula (I) and in whichformula (I) is represented by formula (II), A represents a group offormula (c) and the group of formula (c) has an amino group substitutedby phenyl, may be produced, for example, according to scheme 9 below.

wherein each substituent is as defined above.

The contemplated compound of formula (I) may be synthesized by reactinga 4-chloroquinoline derivative or a corresponding quinazoline derivativewith an o-nitrophenol derivative or a corresponding o-nitroanilinederivative in a suitable solvent, for example, o-dichlorobenzene, or inthe absence of a solvent, for example, at 120 to 180° C. (step (i)above), then reducing the nitro group (step (ii) above), and reactingthe reduction product with a phenylboronic acid derivative (step (iii)above).

10) The compound, which is represented by formula (I) and in whichformula (I) is represented by formula (II), A represents a group offormula (c) and the group of formula (c) has a nitrogen-containingfive-membered heterocyclic group, may be produced, for example,according to scheme 10 below.

wherein each substituent is as defined above.

The contemplated compound of formula (I) may be synthesized by reactinga 4-chloroquinoline derivative or a corresponding quinazoline derivativewith a 5-hydroxyindole derivative or a corresponding 5-aminoindolederivative in a suitable solvent, for example, o-dichlorobenzene, or inthe absence of a solvent, for example, at 120 to 180° C. (step (i)above) and then alkylating the amino group with an alkylating agent, forexample, methyl iodide, or acylating the amino group with an acylatingagent, for example, acetyl chloride (step (ii) above).

11) A given compound, which is represented by formula (I) and in whichformula (I) is represented by formula (II) and A represents a group offormula (c), for example, compound 23, may be produced, for example,according to scheme 11 below.

wherein each substituent is as defined above.

The contemplated compound may be synthesized by reacting a4-chloroquinoline derivative or a corresponding quinazoline derivativewith 3-hydroxy-6-nitrobenzaldehyde derivative or a corresponding5-amino-2-nitrobenzaldehyde derivative in a suitable solvent, forexample, o-dichlorobenzene, or in the absence of a solvent (step (i)above), then reducing the formyl group (step (ii) above), then reducingthe nitro group of the resultant compound (step (iii) above), andreacting the reduction product with a carbonylating agent, for example,triphosgene (step (iv) above).

12) A given compound, which is represented by formula (I) and in whichformula (I) is represented by formula (II) and A represents a group offormula (a1), for example, compound 76, and a given compound in which Arepresents a group of formula (c), for example, compound 165, may beproduced, for example, according to scheme 12 below.

wherein each substituent is as defined above.

The compound of formula (12-1) may be produced by reacting an anisolederivative with an acid chloride in the presence of a Lewis acid (step(i) above) and deprotecting the methoxy group (step (ii) above).

Alternatively, the compound of formula (12-1) may be produced byacylating a phenol derivative with an acylating agent, for example,acetyl chloride or acetic anhydride (step (iii) above) and then reactingthe acylation product with a Lewis acid, for example, scandiumtrifluoromethanesulfonate (step (iv) above).

Next, the contemplated compound, for example, compound 76, may besynthesized by reacting the compound of formula (12-1) with the4-chloroquinoline derivative or a corresponding quinazoline derivativein a suitable solvent, for example, o-dichlorobenzene, or in the absenceof a solvent, for example, at 120 to 180° C. (step (v) above).

The contemplated compound, for example, compound 165, may also besynthesized by reducing the acyl group in the resultant compound (step(vi) above).

13) The compound, which is represented by formula (I) and in whichformula (I) is represented by formula (II) and A represents a pyridinering, that is, a group of formula (b1), may be produced, for example,according to scheme 13 below.

wherein each substituent is as defined above.

The contemplated compound may be synthesized by reacting a4-chloroquinoline derivative or a corresponding quinazoline derivativewith a 3-hydroxypyridine derivative or a corresponding 3-aminopyridinederivative in a suitable solvent, for example, o-dichlorobenzene, in theabsence of a solvent, for example, at 120 to 180° C. (step (i) above).

Alternatively, a method may also be adopted in which a 4-chloroquinolinederivative or a corresponding quinazoline derivative is reacted with a3-hydroxy-2-pyridinecarbaldehyde derivative or a corresponding3-amino-2-pyridinecarbaldehyde derivative in a suitable solvent, forexample, o-dichlorobenzene, or in the absence of a solvent, for example,at 120 to 180° C. (step (ii) above), and the reaction product is thenreacted with an alkylating agent, for example, methylmagnesium bromide(step (iii) above).

Next, the contemplated compound, for example, compound 117, may besynthesized by oxidizing the resultant alcoholic compound, for example,with manganese dioxide as an oxidizing agent (step (iv) above).

Alternatively, another contemplated compound, for example, compound 218,may be synthesized by alkylating the hydroxyl group in the resultantalcoholic compound with an alkylating agent, for example, methyl iodideor ethyl iodide, or by acylating the hydroxyl group in the resultantalcoholic compound with an acylating agent, for example, acetyl chlorideor acetic anhydride (step (v) above). Further, still anothercontemplated compound, for example, compound 214, may be synthesized byreducing this compound, for example, with hydrogen gas/palladiumhydroxide as a reducing agent (step (vi) above).

14) The compound, which is represented by formula (I) and in whichformula (I) is represented by formula (II) and A represents a group offormula (c), particularly a compound in which a substituent such as aniodine atom is present at the o-position of the group of formula (c)represented by A, may be produced, for example, according to scheme 14below.

wherein each substituent is as defined above.

The contemplated compound may be produced by reacting a phenolderivative with iodine (step (i) above), then reacting the allyliodinewith an alkyltin reagent, for example, tri-n-butyl-(2-pyridyl)-tin, oran alkylboronic acid reagent, for example, 3-pyridylboronic acid, in thepresence of a suitable transition metal catalyst, for example, tetrakistriphenylphosphine palladium (step (ii) above), and reacting theresultant phenol derivative with a 4-chloroquinoline derivative or acorresponding quinazolone derivative in a suitable solvent, for example,o-dichlorobenzene, or in the absence of a solvent, for example, at 120to 180° C. (step (iii) above).

15) The compound, which is represented by formula (I) and in whichformula (I) is represented by formula (II) and A represents a group offormula (a1), particularly a compound in which alkoxy is present as asubstituent at the 4-position of the group of formula (a1) representedby A may be produced, for example, according to scheme 15 below.

wherein each substituent is as defined above.

The contemplated compound may be produced by reacting a2,5-dihydroxyphenyl ketone derivative with a benzylating agent, forexample, benzyl bromide (step (i) above), reacting the resultantmonophenol derivative with a 4-chloroquinoline derivative or acorresponding quinazolone derivative in a suitable solvent, for example,o-dichlorobenzene, or in the absence of a solvent, for example, at 120to 180° C. (step (ii) above), then deprotecting the benzyl group in theresultant compound with a suitable acid, for example, methanesulfonicacid/trifluoroacetic acid, or by reduction (step (iii) above), andalkylating the phenolic hydroxyl group in the resultant compound with analkylating agent, for example, ethyl iodide (step (iv) above).

16) The compound, which is represented by formula (I) and in whichformula (I) is represented by formula (II) and A represents a group offormula (a1), particularly a compound in which the group of formula (a1)represented by A has a naphthalene structure, may be produced, forexample, according to scheme 16 below.

wherein

Q represents, for example, chlorine or N,O-dimethylhydroxyamine and

each of the other substituents is as defined above.

In this scheme, the contemplated compound may be synthesized by thefollowing two routes.

(I) An ester derivative is produced by reacting ahydroxynaphthalenecarboxylic acid derivative with a suitable carbonylactivating agent, for example, thionyl chloride (step (i) above) andthen reacting the resultant active form of carboxylic acid derivativewith an alcohol (step (ii) above). Next, the contemplated compound maybe produced by reacting the ester derivative with a 4-chloroquinolinederivative or a corresponding quinazolone derivative in a suitablesolvent, for example, o-dichlorobenzene, or in the absence of a solvent,for example, at 120 to 180° C. (step (iii) above).

(II) A ketone derivative is produced by reacting the active form ofcarboxylic acid derivative produced in step (i) with an alkylatingagent, for example, methylmagnesium bromide (step (iv) above). Next, thecontemplated compound may be produced by reacting the ketone derivativewith a 4-chloroquinoline derivative or a corresponding quinazolonederivative in a suitable solvent, for example, o-dichlorobenzene, or inthe absence of a solvent, for example, at 120 to 180° C. (step (v)above).

17) The compound, which is represented by formula (I) and in whichformula (I) is represented by formula (II) and A represents a group offormula (b1), particularly a compound in which alkoxy is present at theo-position of the group of formula (b1), can be produced, for example,according to scheme 17 below.

wherein each substituent is as defined above.

The contemplated compound may be produced by reacting a2-hydroxypyridine derivative with a 4-chloroquinoline derivative or acorresponding quinazolone derivative in a suitable solvent, for example,o-dichlorobenzene, or in the absence of a solvent, for example, at 120to 180° C. (step (i) above) and alkylating the resultant compound withan alkylating agent, for example, ethyl iodide (step (ii) above).

18) The compound, which is represented by formula (I) and in whichformula (I) is represented by formula (II) and A represents a group offormula (b1), particularly a compound in which alkoxy is present at thep-position of the group of formula (b1), can be produced, for example,according to scheme 18 below.

wherein

R⁸¹ represents a hydrogen atom or C₁₋₄ alkyl,

D represents an oxygen atom, a nitrogen atom, or a sulfur atom, and

each of the other substituents is as defined above.

The contemplated compound may be produced by reacting a 2-chloropyridinederivative with a 4-chloroquinoline derivative or a correspondingquinazolone derivative in a suitable solvent, for example,o-dichlorobenzene, or in the is absence of a solvent, for example, at120 to 180° C. (step (i) above) and reacting the resultant compound witha nucleophilic reagent, for example, methanol (step (ii) above).

19) The compound, which is represented by formula (I) and in whichformula (I) is represented by formula (II) and A represents a group offormula (b1), particularly a compound in which a substituent such as aniodine atom or phenyl is present at the o-position of the group offormula (b1), may be produced, for example, according to scheme 19below.

wherein each substituent is as defined above.

The contemplated compound may be produced by reacting a3-hydroxypyridine derivative with iodine in a suitable solvent, forexample, methanol (step (i) above), reacting the resultant2-iodopyridine derivative with a 4-chloroquinoline derivative or acorresponding quinazolone derivative in a suitable solvent, for example,o-dichlorobenzene, or in the absence of a solvent, for example, at 120to 180° C. (step (ii) above), and then reacting the resultant compoundwith an alkyltin reagent, for example, tri-n-butyl-(2-pyridyl)-tin, oran alkylboronic acid reagent, for example, 3-pyridylboronic acid, in thepresence of a suitable transition metal catalyst, for example, tetrakistriphenylphosphine palladium (step (iii) above).

20) The compound, which is represented by formula (I) and in whichformula (I) is represented by formula (II) and A represents a group offormula (b1), particularly a compound having a cyano group at theo-position of the group of formula (b1), may be produced, for example,according to scheme 20 below.

wherein each substituent is as defined above.

Intermediate 20-1 may be produced by reacting the above startingcompound with a suitable oxidizing agent, for example, manganese dioxide(step (i) above), then reacting the hydroxyl group, remaining unchanged,in the resultant compound with a suitable benzylating agent, forexample, benzyl chloride (step (ii) above). Next, a correspondingcyanopyridine derivative may be produced by reacting intermediate 20-1with an alkoxyamine (step (iii) above). The cyanopyridine derivativethus obtained is deprotected with a suitable acid, for example,methanesulfonic acid/trifluoroacetic acid, or a suitable reducing agent,for example, hydrogen gas/palladium hydroxide (step (iv) above). Thecontemplated compound may be produced by reacting the resultanthydroxypyridine derivative with a 4-chloroquinoline derivative or acorresponding quinazolone derivative in a suitable solvent, for example,o-dichlorobenzene, or in the absence of a solvent, for example, at 120to 180° C. (step (v) above).

21) The compound, which is represented by formula (I) and in whichformula (I) is represented by formula (II) and A represents a group offormula (b1), particularly a compound having a specific heterocyclicgroup at the opposition of the group of formula (b1), for example,compound 256, may be produced, for example, according to scheme 21below.

wherein

R⁸² and R⁸³ represent hydroxyl; cyano; a halogen atom; C₁₋₄ alkoxy;phenyloxy; C₁₋₄ alkylcarbonyl; amino optionally substituted by C₁₋₄alkyl or C₁₋₄ alkylcarbonyl; aminocarbonyl optionally substituted byC₁₋₄ alkyl; or C₁₋₄ alkyl optionally substituted by hydroxyl or ahalogen atom, and each of the other substituents is as defined above.

In this scheme, the contemplated compound may be synthesized by thefollowing two routes.

(I) A ketone derivative may be produced by reacting intermediate 20-1produced according to scheme 20 with an alkyne metal reagent, forexample, 1-propynylmagnesium bromide (step (i) above) and then oxidizingthe hydroxy group in the resultant compound with a suitable oxidizingagent, for example, manganese oxide (step (ii) above). A3-hydroxy-2-isoxazoylpyridine derivative may be produced by reacting theresultant ketone derivative with hydroxyamine (step (iii) above) andthen reacting the resultant compound with a suitable acid, for example,methanesulfonic acid/trifluoroacetic acid (step (iv) above). Thecontemplated compound may be produced by reacting the resultant3-hydroxy-2-isoxazoylpyridine derivative with a 4-chloroquinolinederivative or a corresponding quinazolone derivative in a suitablesolvent, for example, o-dichlorobenzene, or in the absence of a solvent,for example, at 120 to 180° C. (step (v) above).

(II) A ketone derivative may be produced by reacting intermediate 20-1produced according to scheme 20 with an alkyne metal reagent, forexample, 1-propynylmagnesium bromide (step (i) above) and then oxidizingthe hydroxy group in the resultant compound with a suitable oxidizingagent, for example, manganese oxide (step (ii) above). AnN-alkylpyrazole derivative may be produced by reacting the ketonederivative with hydrazine (step (vi) above) and reacting the resultantcompound with an alkylating agent, for example, methyl iodide (step(vii) above). A 3-hydroxypyridine derivative may be produced by reactingthe resultant N-alkylpyrazole derivative with a suitable acid, forexample, methanesulfonic acid/trifluoroacetic acid (step (viii) above).Next, the contemplated compound may be produced by reacting theresultant 3-hydroxypyridine derivative with a 4-chloroquinolinederivative or a corresponding quinazolone derivative in a suitablesolvent, for example, o-dichlorobenzene, or in the absence of a solvent,for example, at 120 to 180° C. (step (ix) above).

22) The compound, which is represented by formula (I) and in whichformula (I) is represented by formula (II) and A represents a group offormula (b1), particularly a compound in which aminomethyl is present atthe o-position of the group of formula (b1), may be produced, forexample, according to scheme 22 below.

wherein

Qx represents a halogen atom, preferably a chlorine atom or a bromineatom, and

each substituent is as defined above.

A quinoline derivative may be produced by reacting a3-hydroxy-2-methylpyridine derivative with a 4-chloroquinolinederivative or a corresponding quinazolone derivative in a suitablesolvent, for example, o-dichlorobenzene, or in the absence of a solvent,for example, at 120 to 180° C. (step (i) above). The contemplatedcompound may be produced by reacting the resultant compound with asuitable base, for example, lithium diisopropylamide to produce acarbanion, reacting the carbanion with a halogenating agent, forexample, N-bromosuccimide (step (ii) above) and then reacting theresultant compound with an amine (step (iii) above).

23 to 25) The compound, which is represented by formula (I) and in whichformula (I) is represented by formula (II) and A represents a group offormula (b1), particularly a compound in which carbonyl is present atthe o-position of the group of formula (b1), may be produced, forexample, by any one of schemes 23 to 25 below.

wherein at least one of Es represents a heteroatom such as a nitrogenatom with the remaining Es representing a carbon atom, or all Esrepresent a carbon atom; and each of the other substituents in thescheme is as defined above.

In this scheme, the contemplated compound may be synthesized by thefollowing two routes.

(I) A ketone derivative may be produced by reacting a3-hydroxy-2-methylquinoline derivative with a suitable oxidizing agent,for example, selenium dioxide (step (i) above), reacting the resultantaldehyde derivative with a metal alkylating agent, for example,methylmagnesium bromide (step (ii) above), and then oxidizing theresultant alcoholic compound with a suitable oxidizing agent, forexample, manganese dioxide (step (iii) above). The contemplated compoundmay be produced by reacting the resultant ketone derivative with a4-chloroquinoline derivative or a corresponding quinazolone derivativein a suitable solvent, for example, o-dichlorobenzene, or in the absenceof a solvent, for example, at 120 to 180° C. (step (vi) above).

(II) A 3-hydroxyquinoline derivative may be produced by reacting an acidchloride derivative with silyl enol ether, for example,4-trimethylsilanyloxy-pent-3-en-2-one (step (iv) above) and thenreacting the resultant ketone derivative with a suitable base, forexample, an aqueous potassium hydroxide solution (step (v) above). Thecontemplated compound may be produced by reacting the 3-hydroxyquinolinederivative with a 4-chloroquinoline derivative or a correspondingquinazolone derivative in a suitable solvent, for example,o-dichlorobenzene, or in the absence of a solvent, for example, at 120to 180° C. (step (vi) above).

wherein

at least any one of Es represents a heteroatom, for example, a nitrogenatom, with the remaining other Es representing a carbon atom, or all Esrepresent a carbon atom,

T represents a halogen atom, preferably a bromine atom, and

each of the other substituents in the scheme is as defined above.

A 2,3-dihydroxyquinoline derivative may be produced by reacting ananiline derivative with chloroacetyl chloride (step (i) above) and thenreacting the resultant amide derivative with a suitable base, forexample, an aqueous potassium hydroxide solution (step (ii) above). A2-hydroxyquinoline derivative may be produced by reacting the resultant2,3-dihydroxyquinoline derivative with a 4-chloroquinoline derivative ora corresponding quinazolone derivative in a suitable solvent, forexample, o-dichlorobenzene, or in the absence of a solvent, for example,at 120 to 180° C. (step (iii) above). A 2-haloquinoline derivative maybe produced by reacting the resultant 2-hydroxyquinoline derivative witha suitable halogenating agent, for example, tetrabutylammonium bromide(step (iv) above). The contemplated compound may be produced by reactingthe 2-haloquinoline derivative with an alkyltin reagent, for example,tri-n-butyl-(2-pyridyl)-tin, or an alkylboronic acid reagent, forexample, 3-pyridylboronic acid, in the presence of a suitable transitionmetal catalyst, for example, tetrakis triphenylphosphine palladium (step(v) above).

wherein at least any one of Es represents a heteroatom, for example, anitrogen atom, with the remaining other Es representing a carbon atom,or all Es represent a carbon atom, and each of the other substituents inthe scheme is as defined above.

An amide derivative may be produced by reacting an aniline derivativewith pivaloyl chloride (step (i) above). Next, an o-acylanilinederivative may be produced by reacting the resultant amide derivativewith a suitable alkyllithium, for example, n-butyllithium to give ananion, reacting the anion with an acylating agent, for example,N,N-dimethylformamide (step (ii) above), then deprotecting the pivaloylgroup with a suitable acid, for example, hydrochloric acid (step (iii)above). The contemplated compound may be produced by reacting theo-acylaniline derivative with a methyl ketone derivative (step (iv)above) to give a 3-hydroxyquinoline derivative and then reacting the3-hydroxyquinoline derivative with a 4-chloroquinoline derivative or acorresponding quinazolone derivative in a suitable solvent, for example,o-dichlorobenzene, or in the absence of a solvent, for example, at 120to 180° C. (step (v) above).

26) The compound, which is represented by formula (I) and in whichformula (I) is represented by formula (II) and A represents a group offormula (c), for example, compound 297, may be produced, for example,according to scheme 26 below.

wherein each substituent is as defined above.

The contemplated compound may be produced by reacting a6-benzyloxy-4-chloroquinoline derivative with a suitable reducing agent,for example, hydrogen gas/palladium hydroxide (step (i) above) to give a6-hydroxyquinoline derivative and reacting the 6-hydroxyquinolinederivative with a 4-chloroquinoline derivative or a correspondingquinazolone derivative in a suitable solvent, for example,o-dichlorobenzene, or in the absence of a solvent, for example, at 120to 180° C. (step (ii) above).

27) The compound, which is represented by formula (I) and in whichformula (I) is represented by formula (II) and A represents a group offormula (c), for example, compound 299, may be produced, for example,according to scheme 27 below.

wherein each substituent is as defined above.

A trifluoromethanesulfonate derivative may be produced by reacting a7-benzyloxy-4-chloroquinoline derivative with a suitable reducing agent,for example, hydrogen gas/palladium hydroxide to give an alcohol (step(i) above) and then reacting the alcohol with trifluoromethanesulfonicanhydride (step (ii) above) to give a trifluoromethanesulfonatederivative. A quinoline derivative may be produced by reacting thetrifluoromethanesulfonate derivative with an alkyltin reagent, forexample, tri-n-butyl-(2-pyridyl)-tin or an alkylboronic acid reagent,for example, 3-pyridylboronic acid in the presence of a suitabletransition metal catalyst, for example, tetrakis triphenylphosphinepalladium (step (iii) above) and reacting the resultant compound with asuitable oxidizing agent, for example,2,3-dichloro-5,6-dicyano-1,4-benzoquinone, to give a quinolinederivative (step (iv) above). Next, a 6-hydroxyquinoline derivative maybe produced by reacting the quinoline derivative with a suitablereagent, for example, boron tribromide (step (v) above). Thecontemplated compound may be produced by reacting the 6-hydroxyquinolinederivative with a 4-chloroquinoline derivative or a correspondingquinazolone derivative in a suitable solvent, for example,o-dichlorobenzene, or in the absence of a solvent, for example, at 120to 180° C. (step (vi) above).

28 and 29) The compound, which is represented by formula (I) and inwhich formula (I) is represented by formula (II) and A represents agroup of formula (c), particularly a compound in which the group offormula (c) has an isoquinoline structure, may be produced, for example,according to scheme 28 or 29 below.

wherein each substituent is as defined above.

A 6-methoxyisoquinoline derivative may be produced by reacting a4-methoxybenzaldehyde derivative with a dimethoxyalkylamine derivativeto give an imine derivative (step (i) above) and reacting the iminederivative with a suitable Lewis acid, for example, titaniumtetrachloride, to give a 6-methoxyisoquinoline derivative (step (ii)above). A 6-hydroxyisoquinoline derivative may be produced by reactingthe 6-methoxyisoquinoline derivative with a suitable reagent, forexample, boron tribromide (step (iii) above). Next, the contemplatedcompound may be produced by reacting the 6-hydroxyquinoline derivativewith a 4-chloroquinoline derivative or a corresponding quinazolonederivative in a suitable solvent, for example, o-dichlorobenzene, or inthe absence of a solvent, for example, at 120 to 180° C. (step (iv)above).

wherein each substituent is as defined above.

A 6-methoxyisoquinoline derivative may be produced by reacting a3-bromo-4-methoxybenzaldehyde derivative with a dimethoxyalkylaminederivative to give an imine derivative (step (i) above) and thenreacting the imine derivative with a suitable Lewis acid, for example,titanium tetrachloride, to give a 6-methoxyisoquinoline derivative (step(ii) above). A 6-hydroxyisoquinoline derivative may be produced byreacting the 6-methoxyisoquinoline derivative with a suitable reagent,for example, boron tribromide (step (iii) above). Next, the6-hydroxyquinoline derivative is reacted with a 4-chloroquinolinederivative or a corresponding quinazolone derivative in a suitablesolvent, for example, o-dichlorobenzene, or in the absence of a solvent,for example, at 120 to 180° C. (step (iv) above). The contemplatedcompound may be produced by reacting the resultant compound with analkyltin reagent, for example, tri-n-butyl-(2-pyridyl)-tin, or analkylboronic acid reagent, for example, 3-pyridylboronic acid, in thepresence of a suitable transition metal catalyst, for example, tetrakistriphenylphosphine palladium (step (v) above).

30) The compound, which is represented by formula (I) and in whichformula (I) is represented by formula (II) and A represents a group offormula (c), for example, compound 305, may be produced, for example,according to scheme 30 below.

wherein each substituent is as defined above.

An alkyl 3-alkoxybenzoate derivative may be produced by reacting a3-hydroxybenzoic acid derivative with an alkylating agent, for example,methyl iodide, (step (i) above). An aniline derivative may be producedby reacting the alkyl 3-alkoxybenzoate derivative with nitric acid inthe presence of a suitable acid, for example, acetic acid (step (ii)above) and then reducing the resultant nitro group with a suitablereducing agent, for example, hydrogen gas/palladium hydroxide to give ananiline derivative (step (iii) above). A 4-chloroquinazoline derivativemay be produced by reacting the amino group in the aniline derivativewith an alkylamide (step (iv) above) and then reacting the resultantcompound with a suitable halogenating agent, for example, phosphorusoxychloride (step (v) above). Next, a 6-hydroxyquinazoline derivativemay be produced by reducing the 4-chloroquinazoline derivative with asuitable reducing agent, for example, hydrogen gas/palladium hydroxide(step (vi) above) and then reacting the resultant compound with asuitable reagent, for example, boron tribromide (step (vii) above). Thecontemplated compound may be produced by reacting the6-hydroxyquinazoline derivative with a 4-chloroquinoline derivative or acorresponding quinazolone derivative in a suitable solvent, for example,o-dichlorobenzene, or in the absence of a solvent, for example, at 120to 180° C. (step (viii) above).

31) The compound, which is represented by formula (I) wherein R′represents a group other than —OR″, may be produced, for example,according to scheme 31 below.

wherein each substituent is as defined above.

A trifluoromethanesulfonate derivative may be produced by reacting a7-benzyloxy-4-chloroquinoline derivative or a corresponding quinazolonederivative with a suitable acid, for example, methanesulfonicacid/trifluoroacetic acid to give an alcohol (step (i) above) and thenreacting the alcohol with trifluoromethanesulfonic anhydride (step (ii)above). The trifluoromethanesulfonate derivative is reacted with anamine or an alkene in the presence of a suitable transition metalcatalyst, for example, tetrakis triphenylphosphine palladium (step (iii)above). The contemplated compound may be produced by reacting theresultant compound with a phenol derivative or a corresponding anilinederivative in a suitable solvent, for example, o-dichlorobenzene, or inthe absence of a solvent, for example, at 120 to 180° C. (step (iv)above).

32) The compound, which is represented by formula (I) wherein Rrepresents a group other than methoxy, may be produced, for example,according to scheme 32 below.

wherein each substituent is as defined above.

A 6-benzyloxy-4-chloroquinoline derivative or a correspondingquinazolone derivative is reacted with a phenol derivative or acorresponding aniline derivative in a suitable solvent, for example,o-dichlorobenzene, or in the absence of a solvent, for example, at 120to 180° C. (step (i) above). Next, a 6-hydroxyquinoline derivative maybe produced by reacting the resultant compound with a suitable acid, forexample, methanesulfonic acid/trifluoroacetic acid (step (ii) above).The contemplated compound may be produced by reacting the6-hydroxyquinoline derivative with an alkylating agent, for example,1-bromo-2-chloroethane (step (iii) above).

33) The compound, which is represented by formula (I) and in whichformula (I) is represented by formula (II) and A represents a group offormula (a3), may be produced, for example, according to scheme 33below.

wherein each substituent is as defined above.

The contemplated compound may be produced by reacting a4-chloroquinoline derivative or a corresponding quinazoline derivativewith a phenol derivative or a corresponding aniline derivative in asuitable solvent, for example, o-dichlorobenzene, or in the absence of asolvent, for example, at 120 to 180° C. (step (i) above) and thenreacting the resultant compound with an amine derivative (step (ii)above).

34) The compound, which is represented by formula (I) and in whichformula (I) is represented by formula (II) and A represents a group offormula (b1), particularly a compound in which an aromatic substituentis present at the o-position of the group of formula (b1) and methyl ispresent at the m-position and p-position, may be produced, for example,according to scheme 34 below.

wherein each substituent is as defined above.

In this scheme, the contemplated compound may be synthesized by thefollowing two routes.

(I) An alcohol derivative is produced by reacting a furfural derivativewith an alkyl metal reagent, for example, phenylmagnesium bromide (step(i) above). A ketone derivative may be produced by oxidizing the alcoholderivative with a suitable oxidizing agent, for example, manganesedioxide (step (ii) above). Next, a 3-hydroxy-pyridine derivative may beproduced by reacting the ketone derivative with ammonia (step (iv)above). Further, the contemplated compound may be produced by reactingthe 3-hydroxypyridine derivative with a 4-chloroquinoline derivative ora corresponding quinazolone derivative in a suitable solvent, forexample, o-dichlorobenzene, or in the absence of a solvent, for example,at 120 to 180° C.

(II) A ketone derivative may be produced by reacting a furan derivativewith an alkyllithium reagent, for example, n-butyllithium, and thenreacting the resultant compound with an acylating agent, for example,benzoyl chloride (step (iii) above). A 3-hydroxypyridine derivative maybe produced by reacting the ketone derivative with ammonia (step (iv)above). Next, the contemplated compound may be produced by reacting the3-hydroxypyridine derivative with a 4-chloroquinoline derivative or acorresponding quinazolone derivative in a suitable solvent, for example,o-dichlorobenzene, or in the absence of a solvent, for example, at 120to 180° C. (step (v) above).

Use of Compounds/Pharmaceutical Composition

Compounds according to the present invention inhibit the action of TGFβon cells in vitro (see Test Example 1).

As described in the section of the background art, the inhibition ofTGFβ has been regarded as useful for the prophylaxis or therapy of alldiseases involving fibrosis including chronic renal diseases. Examplesof references showing a correlation between TGFβ and these diseases areas described in the section of the background art.

Further, compounds according to the present invention actually exhibitedanti-fibrosis activity in vivo (see Test Examples 2 to 4).

Accordingly, the compounds according to the present invention can beused for the prophylaxis or therapy of diseases for which the TGFβinhibitory activity is effective therapeutically.

The term “TGFβ inhibitory activity” as used herein means that thecompound has the activity of inhibition against the activity of TGFβ, akind of cytokine, within cells or tissues.

According to the present invention, there is provided a method forpreventing or treating a disease for which TGFβ inhibition is effectivetherapeutically, comprising the step of administering a therapeuticallyor prophylactically effective amount of the compound according to thepresent invention to a patient. The term “patient” as used herein refersto a patient who should undergo therapy of a disease for which TGFβinhibition is effective therapeutically or prophylactically.

According to the present invention, there is provided use of thecompound according to the present invention, for the manufacture of atherapeutic or prophylactic agent for a disease for which TGFβinhibition is effective therapeutically or prophylactically.

According to the present invention, there is provided a pharmaceuticalcomposition comprising the compound according to the present inventionor a pharmaceutically acceptable salt or solvate thereof. Thepharmaceutical composition according to the present invention can beused for the prophylaxis or therapy of diseases for which the TGFβinhibitory activity is effective therapeutically or prophylactically.

The diseases for which the TGFβ inhibitory activity is effectivetherapeutically or prophylactically are preferably diseases involvingfibrosis of an organ or a tissue.

Diseases for which TGFβ inhibition is effective therapeutically orprophylactically include chronic renal disease, acute renal disease,hepatic fibrosis, cirrhosis, pulmonary fibrosis, scleroderma, woundhealing, arthritis, congestive cardiac disease, ulcer, ocular disorder,cornea disorder, diabetic nephropathy, peritoneal sclerosis, arterialsclerosis, peritoneal adhesion, and subdermal adhesion.

In another preferred embodiment of the present invention, the diseasefor which TGFβ inhibition is effective therapeutically orprophylactically is a malignant tumor.

In still another preferred embodiment of the present invention, thecompound or pharmaceutical composition according to the presentinvention may be used for in vitro amplification of cells. The cells arepreferably hematopoietic stem cells.

Accordingly, in a further preferred embodiment of the present invention,there is provided a method for amplifying cells in vitro, comprising thestep of addition of the compound according to the present invention or apharmaceutically acceptable salt or solvate thereof in an amounteffective for promoting cell amplification, into targeted cells.

In a still further embodiment of the present invention, there isprovided an accelerator for in vitro amplification of cells, comprisingthe compound according to the present invention or a pharmaceuticallyacceptable salt or solvate thereof.

In another embodiment of the present invention, there is provided a TGFβinhibitor comprising the compound according to the present invention ora pharmaceutically acceptable salt or solvate thereof.

The compounds according to the present invention can be administered tohuman and non-human animals either orally or parenterally byadministration routes, for example, intravenous administration,intramuscular administration, subcutaneous administration, rectaladministration, or percutaneous administration.

Therefore, the pharmaceutical composition comprising the compoundaccording to the present invention is formulated into suitable dosageforms according to the administration routes. Specifically, oralpreparations include tablets, capsules, powders, granules, and syrups,and parental preparations include injections, suppositories, tapes, andointments.

These various drug formulations may be prepared by conventional methods,for example, with pharmaceutically acceptable carriers, that is,commonly used excipients, disintegrants, binders, lubricants, colorants,and diluents.

Excipients include, for example, lactose, glucose, corn starch, sorbit,and crystalline cellulose. Disintegrants include, for example, starch,sodium alginate, gelatin powder, calcium carbonate, calcium citrate, anddextrin. Binders include, for example, dimethylcellulose, polyvinylalcohol, polyvinyl ether, methylcellulose, ethylcellulose, gum arabic,gelatin, hydroxypropylcellulose, and polyvinyl pyrrolidone. Lubricantsinclude, for example, talc, magnesium stearate, polyethylene glycol, andhydrogenated vegetable oils.

In preparing the injectable solutions, if necessary, for example,buffers, pH adjustors, stabilizers, tonicity agents, and preservativesmay be added.

The content of the compound according to the present invention in thepharmaceutical composition according to the present invention may varydepending upon the dosage form. In general, however, the content is 0.5to 50% by weight, preferably 1 to 20% by weight, based on the wholecomposition.

The dose may be appropriately determined in consideration of, forexample, the age, weight, sex, difference in diseases, and severity ofcondition of individual patients, for example, in the range of 0.1 to100 mg/kg, preferably in the range of 0.1 to 30 mg/kg. This dose isadministered at a time daily or divided doses of several times daily.

The compound according to the present invention may be administered incombination with other medicament, for example, a carcinostatic agent.In this case, the compound according to the present invention may beadministered simultaneously with or after or before the administrationof other medicament. The type, administration intervals and the like ofthe carcinostatic agent may be determined depending upon the type ofcancer and the condition of patients.

When the compound according to the present invention is used in in-vitroamplification of cells, a proper medium may be selected or prepared, forexample, according to the type of cells. The amount of the compoundaccording to the present invention added to the medium may be properlydetermined depending upon the type, application and the like of thecells. The addition amount is preferably 0.01 to 50 μM, more preferably0.1 to 20 μM.

In another one embodiment of the present invention, there is provided amethod for inhibiting the action of TGFβ on cells, comprising the stepof applying an effective amount of the compound according to the presentinvention to cells present in vitro or in the body.

EXAMPLES

The present invention is further illustrated by the following Examplesthat are not intended as a limitation of the invention.

Example 1

In the following Examples, Production Example 1 is Production Example ofintermediate 1 in scheme 3, Production Example 2 is Production Exampleof intermediate 2 in scheme 4, and Production Examples 3 and 4 arerespectively Production Examples of intermediates 3 and 4 in scheme 5.

Production Example 12-[(6,7-Dimethoxy-4-quinolyl)oxy]-5-methylbenzaldehyde (intermediate 1)

4-Chloro-6,7-dimethoxyquinoline (113 mg), 2-hydroxy-5-methylbenzaldehyde(344 mg), and 4-dimethylaminopyridine (313 mg) were suspended ino-dichlorobenzene (5 ml), and the suspension was stirred at 160° C. for2 hr. The reaction solution was cooled to room temperature, and thesolvent was then removed therefrom by distillation under the reducedpressure. Chloroform was added to the residue. The organic layer waswashed with a 1 N aqueous sodium hydroxide solution and saturated brineand was dried over anhydrous magnesium sulfate. The solvent was removedtherefrom by distillation under the reduced pressure. The residue waspurified by column chromatography using chloroform to give the titlecompound (157 mg, yield 96%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.46 (s, 3H), 4.06 (s, 3H), 4.06 (s, 3H),6.44 (d, J=5.1 Hz, 1H), 7.10 (d, J=8.3 Hz, 1H), 7.45 (s, 1H), 7.49 (m,1H), 7.57 (s, 1H), 7.83 (d, J=1.9 Hz, 1H), 8.51 (d, J=1.5 Hz, 1H), 10.28(s, 1H)

Mass spectrometric value (ESI−MS, m/z): 324 (M+1)⁺

Production Example 2 2-(6,7-Dimethoxyquinolin-4-yloxy)-5-methoxybenzoicacid (intermediate 2)

Ethyl 2-(6,7-dimethoxyquinolin-4-yloxy)-5-methoxy-benzoate (143 mg) andlithium hydroxide (78 mg) were suspended in a mixed solvent composed ofethanol (10 ml) and water (1 ml), and the suspension was stirred at roomtemperature overnight. The solvent was then removed therefrom bydistillation under the reduced pressure. Water was added to the residue,and the resultant solution was neutralized with 12N hydrochloric acid.The mixture was then extracted with chloroform. The chloroform layer waswashed with water and saturated brine and was dried over anhydroussodium sulfate. The solvent was removed therefrom by distillation underthe reduced pressure to give the title compound (140 mg, yield 100%).

¹H-NMR (CDCl₃-d₁, 400 MHz): δ 3.73 (s, 3H), 3.80 (s, 3H), 3.95 (s, 3H),6.44 (d, J=5.6 Hz, 1H), 6.91-7.19 (m, 3H), 7.34 (s, 1H), 7.46 (s, 1H),7.60 (s, 1H), 8.10 (d, J=5.6 Hz, 1H), 13.26 (brs, 1H)

Mass spectrometric value (ESI−MS, m/z): 356 (M⁺+1)

Production Example 3[2-(7-Benzyloxy-6-methoxyquinolin-4-yloxy)-5-methoxyphenyl]ethanone(intermediate 3)

7-Benzyloxy-4-chloro-6-methoxyquinoline (3.00 mg),5-methoxy-2-acetophenone (6.7 g), and 4-dimethylaminopyridine (4.9 g)were suspended in o-dichlorobenzene (30 ml), and the suspension wasstirred at 180° C. for 2 hr. The reaction solution was cooled to roomtemperature. Water was added to the cooled reaction solution, and themixture was extracted with chloroform. The chloroform layer was washedwith water and saturated brine and was dried over anhydrous sodiumsulfate. The solvent was removed therefrom by distillation under thereduced pressure, and the residue was purified by thin layerchromatography using acetone-hexane to give the title compound (2.53 g,yield 59%).

¹H-NMR (CDCl₃-d₁, 400 MHz): δ 2.42 (s, 3H), 3.82 (s, 3H), 3.98 (s, 3H),5.26 (s, 2H), 6.28 (d, J=5.6 Hz, 1H), 7.03-7.08 (m, 1H), 7.23-7.51 (m,9H), 8.39 (d, J=5.6 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 430 (M⁺+1)

Production Example 4[2-(7-Hydroxy-6-methoxyquinolin-4-yloxy)-5-methoxyphenyl]ethanone(intermediate 4)

[2-(7-Benzyloxy-6-methoxyquinolin-4-yloxy)-5-methoxyphenyl]-ethanone(intermediate 3) (2.52 g) was suspended in a mixed solution composed ofmethanesulfonic acid (3.0 ml) and trifluoroacetic acid (50 ml), and thesuspension was stirred at 70° C. for 0.5 hr. The solvent was removedtherefrom by distillation under the reduced pressure. Water was added tothe residue, and the mixture was neutralized with sodiumhydrogencarbonate powder. The mixture was then extracted withchloroform. The chloroform layer was then washed with water andsaturated brine and was dried over anhydrous sodium sulfate. The solventwas removed therefrom by distillation under the reduced pressure. Theresidue was purified by column chromatography using acetone-hexane togive the title compound (1.23 g, yield 62%).

¹H-NMR (DMSO-d₆, 400 MHz): δ 2.50 (s, 3H), 3.91 (s, 3H), 4.00 (s, 3H),6.35 (d, J=5.2 Hz, 1H), 7.34 (m, 3H), 7.42 (s, 1H), 7.61 (s, 1H), 8.44(d, J=5.2 Hz, 1H), 10.24 (brs, 1H)

Mass spectrometric value (ESI−MS, m/z): 338 (M⁺−1)

Example 2

Compounds of formula (I) according to the present invention wereproduced as follows.

The compounds thus produced are shown in tables below in relationship toschemes applied to the production thereof.

TABLE A-1 Scheme Compound  2 1 to 5, 12, 13, 15 to 17, 19, 22, 24, 26 to42, 57, 62 to 72, 74, 75, 77, 78, 161, 162, and 425  3 9 to 11, 18, 43to 56, 58 to 61, 73, 166, 172, 181, 188 to 192, 293, 306 to 311, and 418to 420  4 79 to 114  5 118 to 160, 312 to 409, and 440 to 469  6 163  77, and 8  8 6  9 14 10 20, and 21 11 23 12 76, 165, 173, 174, and 182 to187 13 115 to 117, 202, 203, 205, 206, 208 to 210, 214, 215, 217 to 221,275, and 276

TABLE A-2 Scheme Compound 14 164, 167 to 171, 294 to 296, 298, and 30215 175 to 180 16 200, and 201 17 204, 222, and 280 18 207 19 211, 212,216, 223 to 255, 259, 261 to 267, 291, 434, and 438 20 213 21 256 to 25822 277 23 278, and 279 24 281, 282, 284, and 287 to 289 25 283, 285,286, 290, 292, 421 to 424, 426 to 428, 436, and 439 26 297 27 299 28 30029 301, 303, and 304 30 305 31 410 to 414 32 415 to 417 33 193 to 199 34260, 268 to 274, 429 to 433, 435, and 437

Compound 1 4-(2-Benzylphenoxy)-6,7-dimethoxyquinoline

4-Chloro-6,7-dimethoxyquinoline (230 mg) and 2-benzylphenol (254 mg)were suspended in o-dichlorobenzene (1 ml), and the suspension wasstirred at 180° C. overnight. The reaction solution was cooled to roomtemperature, and water was added thereto. The mixture was extracted withethyl acetate. The ethyl acetate layer was then washed with water andsaturated brine and was dried over anhydrous sodium sulfate. The solventwas then removed therefrom by distillation under the reduced pressure,and the residue was purified by thin layer chromatography using ethylacetate-hexane to give the title compound (40 mg, yield 10%).

¹H-NMR (CDCl₃, 400 MHz): δ 3.90 (s, 2H), 3.96 (s, 3H), 4.05 (s, 3H),6.31 (d, J=5.4 Hz, 1H), 7.07-7.37 (m, 9H), 7.40 (s, 1H), 7.44 (s, 1H),8.42 (d, J=5.1 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 372 (M+1)⁺

Compound 2 6,7-Dimethoxy-4-[2-(1-propenyl)phenoxy]quinoline

4-Chloro-6,7-dimethoxyquinoline (100 mg), 2-(1-propenyl)phenol (231 μl),and 4-dimethylaminopyridine (220 mg) were suspended in o-dichlorobenzene(1 ml), and the suspension was stirred at 140° C. for 7 hr. The reactionsolution was cooled to room temperature, and the solvent was thenremoved therefrom by distillation under the reduced pressure.Thereafter, water was added to the residue, and the mixture wasextracted with chloroform. The chloroform layer was washed with waterand was dried over anhydrous sodium sulfate. The solvent was removedtherefrom by distillation under the reduced pressure, and the residuewas purified by column chromatography using acetone-hexane to give thetitle compound (137 mg, yield 43%).

¹H-NMR (CDCl₃, 400 MHz): δ 1.76-1.85 (m, 3H), 4.06 (m, 6H), 6.27-6.35(m, 2H), 6.44-6.48 (m, 1H), 7.06-7.17 (m, 1H), 7.24-7.64 (m, 5H), 8.45(m, 1H)

Mass spectrometric value (ESI−MS, m/z): 322 (M+1)⁺

Compound 3 4-(2-Chloro-4-methylphenoxy)-6,7-dimethoxyquinoline

4-Chloro-6,7-dimethoxyquinoline (0.89 g), 2-chloro-4-methylphenol (1.0g), and 4-dimethylaminopyridine (1 g) were suspended ino-dichlorobenzene (10 ml), and the mixture was stirred at 160° C. for 2hr. The reaction solution was cooled to room temperature, and water wasthen added thereto. The mixture was extracted with ethyl acetate. Theethyl acetate layer was then washed with water and saturated brine, andwas dried over anhydrous sodium sulfate. The solvent was removedtherefrom by distillation under the reduced pressure, and the residuewas purified by column chromatography using acetone-chloroform to givethe title compound (0.92 g, yield 70%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.40 (s, 3H), 4.05 (s, 3H), 4.07 (s, 3H),6.31 (d, J=5.1 Hz, 1H), 7.13 (d, J=8.1 Hz, 1H), 7.16 (m, 1H), 7.35 (m,1H), 7.44 (s, 1H), 7.61 (s, 1H), 8.47 (d, J=5.1 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 330 (M+1)⁺

Compound 4 4-(2-Bromo-4-methylphenoxy)-6,7-dimethoxyquinoline

4-Chloro-6,7-dimethoxyquinoline (1.33 g) and 2-bromo-4-methylphenol (2.5ml) were dissolved in o-dichlorobenzene (3 ml), and the solution wasstirred at 160° C. for 5 hr. The reaction solution was cooled to roomtemperature, and water was then added to the reaction solution. Themixture was extracted with ethyl acetate. The ethyl acetate layer wasthen washed with aqueous sodium hydroxide solution and saturated brineand was dried over anhydrous sodium sulfate. The solvent was removedtherefrom by distillation under the reduced pressure, and the residuewas purified by column chromatography on silica gel usingacetone-chloroform to give the title compound (1.83 g, yield 82%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.38 (s, 3H), 4.03 (s, 3H), 4.04 (s, 3H),6.28 (d, J=5.4 Hz, 1H), 7.09 (d, J=8.0 Hz, 1H), 7.17 (m, 1H), 7.41 (s,1H), 7.50 (d, J=1.9 Hz, 1H), 7.58 (s, 1H), 8.45 (d, J=5.1 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 374 (M+1)⁺

Compound 5 6,7-Dimethoxy-4-(2,4-dimethylphenoxy)quinoline hydrochloride

4-Chloro-6,7-dimethoxyquinoline (200 mg) and 2,4-dimethylphenol (0.267ml) were suspended in diethylene glycol dimethyl ether (0.1 ml), and thesuspension was stirred at 180° C. for 1.5 hr. The reaction solution wascooled to room temperature, and an aqueous sodium hydroxide solution wasthen added to the reaction solution. The mixture was extracted withchloroform. The chloroform layer was then washed with saturated brineand was dried over anhydrous sodium sulfate. The solvent was removedtherefrom by distillation under the reduced pressure. The residue waspurified by column chromatography on silica gel using acetone-chloroformto give 4-(2,4-dimethylphenoxy)-6,7-dimethoxyquinoline (127 mg, yield46%).

4-(2,4-Dimethylphenoxy)-6,7-dimethoxyquinoline (99 mg) was dissolved ina 10% hydrochloric acid/methanol solution, and the solution was stirredat room temperature for 15 min. The solvent was removed therefrom bydistillation under the reduced pressure, and the residue was washed withethyl acetate to give the title compound (94 mg, yield 85%).

¹H-NMR (CD₃OD, 400 MHz): δ 2.11 (s, 3H), 2.37 (s, 3H), 4.04 (s, 3H),4.04 (s, 3H), 6.66 (d, J=6.6 Hz, 1H), 7.21 (m, 1H), 7.23 (m, 1H), 7.31(m, 1H), 7.63 (s, 1H), 7.78 (s, 1H), 8.75 (d, J=6.6 Hz, 1H)

Compound 66,7-Dimethoxy-4-[4-methyl-2-(piperidinomethyl)phenoxy]-quinoline

2-[(6,7-Dimethoxy-4-quinolyl)oxy]-5-methylbenzaldehyde (88.6 mg) wasdissolved in methanol (5 ml). Piperidine (250 mg) was then added to thesolution, and the mixture was stirred at room temperature for 10 min.Further, sodium borohydride (17.5 mg) was added thereto, and the mixturewas stirred at room temperature for 20 min. Ethyl acetate and water wereadded to the reaction solution, and the mixture was extracted with ethylacetate. The ethyl acetate layer was then washed with saturated brineand was dried over anhydrous sodium sulfate. The solvent was removedtherefrom by distillation under the reduced pressure, and the residuewas purified by thin layer chromatography using acetone-hexane to givethe title compound (71 mg, yield 66%).

¹H-NMR (CDCl₃, 400 MHz): δ 1.25-1.49 (m, 6H), 2.30-2.38 (m, 4H), 2.40(s, 3H), 3.39 (s, 2H), 4.06 (s, 6H), 6.30 (d, J=5.4 Hz, 1H), 7.01 (d,J=8.1 Hz, 1H), 7.14 (dd, J=1.7 Hz, 8.0 Hz, 1H), 7.39 (d, J=1.4 Hz, 1H),7.44 (s, 1H), 7.61 (s, 1H), 8.44 (d, J=5.4 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 393 (M+1)⁺

Compound 76,7-Dimethoxy-4-{4-methoxy-2-[(E)-2-phenyl-1-ethenyl]phenoxy}quinoline

4-Chloro-6,7-dimethoxyquinoline (2.23 g),2-hydroxy-5-methoxybenzaldehyde (6.08 g), and 4-dimethylaminopyridine(4.88 g) were suspended in monochlorobenzene (40 ml), and the suspensionwas stirred at 130° C. overnight. The reaction solution was cooled toroom temperature, and water was then added thereto. The mixture wasextracted with ethyl acetate. The ethyl acetate layer was then washedwith water and saturated brine and was dried over anhydrous sodiumsulfate. The solvent was removed therefrom by distillation under thereduced pressure, and the residue was purified by chromatography onsilica gel using ethyl acetate-hexane for development to give2-[(6,7-dimethoxy-4-quinolyl)oxy]-5-methoxybenzaldehyde (2.72 g).

Sodium hydride (60 wt % oil, 52 mg) was dissolved in anhydroustetrahydrofuran (1 ml), and a solution (0.5 ml) of benzylphosphonic acid(114 mg) in tetrahydrofuran was added dropwise to the solution at 0° C.under an argon atmosphere. The mixture was stirred at 0° C. for 30 min,and a solution (0.5 ml) of2-[(6,7-dimethoxy-4-quinolyl)oxy]-5-methoxybenzaldehyde (100 mg) intetrahydrofuran was then added dropwise thereto. The reaction mixturewas stirred at room temperature for one hr, and water (1 ml) was thenadded dropwise thereto to stop the reaction. The mixture was extractedwith ethyl acetate, and the ethyl acetate layer was then washed withwater and saturated brine and was dried over anhydrous sodium sulfate.The solvent was removed therefrom by distillation under the reducedpressure, and the residue was purified by chromatography on silica gelusing ethyl acetate-hexane for development to give the title compound(100 mg, yield 80%).

¹H-NMR (CDCl₃, 400 MHz): δ 3.85 (s, 3H), 4.00 (s, 3H), 4.01 (s, 3H),6.29 (d, J=5.4 Hz, 1H), 6.84 (dd, J=3.2 Hz, 9.0 Hz, 1H), 7.01 (d, J=8.8Hz, 1H), 7.06 (d, J=7.4 Hz, 1H), 7.11-7.28 (m, 7H), 7.43 (s, 1H), 7.61(s, 1H), 8.38 (d, J=5.4 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 414 (M+1)⁺

Compound 8 Ethyl(E)-3-{2-[(6,7-dimethoxy-4-quinolyl)oxy]-5-methoxyphenyl}-2-methyl-2-propenoate

4-Chloro-6,7-dimethoxyquinoline (2.23 g),2-hydroxy-5-methoxybenzaldehyde (6.08 g), and 4-dimethylaminopyridine(4.88 g) were suspended in monochlorobenzene (40 ml), and the suspensionwas stirred at 130° C. overnight. The reaction solution was cooled toroom temperature, and water was then added to the reaction solution. Themixture was extracted with ethyl acetate. The ethyl acetate layer wasthen washed with water and saturated brine and was dried over anhydroussodium sulfate. The solvent was removed therefrom by distillation underthe reduced pressure, and the residue was purified by chromatography onsilica gel using ethyl acetate-hexane for development to give2-[(6,7-dimethoxy-4-quinolyl)oxy]-5-methoxybenzaldehyde (2.72 g).

Sodium hydride (60 wt % oil, 52 mg) was dissolved in anhydroustetrahydrofuran (1 ml), and a solution (0.5 ml) of triethyl2-phosphonopropionate (119 mg) in tetrahydrofuran was added dropwisethereto under an argon atmosphere at 0° C. The mixture was stirred at 0°C. for 30 min, and a solution (0.5 ml) of2-[(6,7-dimethoxy-4-quinolyl)oxy]-5-methoxybenzaldehyde (100 mg) intetrahydrofuran was then added dropwise thereto. The reaction mixturewas stirred at room temperature for one hr, and water (1 ml) was thenadded dropwise to stop the reaction. The mixture was extracted withethyl acetate, and the ethyl acetate layer was then washed with waterand saturated brine and was dried over anhydrous sodium sulfate. Thesolvent was removed therefrom by distillation under the reducedpressure, and the residue was purified by chromatography on silica gelusing ethyl acetate-hexane for development to give the title compound(64 mg, yield 50%).

¹H-NMR (CDCl₃, 400 MHz): δ 1.05 (t, J=7.2 Hz, 3H), 1.99 (s, 3H), 3.80(s, 3H), 3.98 (s, 6H), 4.00 (q, J=7.2 Hz, 2H), 6.16-6.24 (m, 1H),6.87-6.94 (m, 2H), 7.05 (d, J=8.5 Hz, 1H), 7.32-7.40 (m, 1H), 7.48 (s,1H), 7.50 (s, 1H), 8.37 (d, J=5.1 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 424 (M+1)⁺

Compound 91-{2-[(6,7-Dimethoxy-4-quinolyl)oxy]-5-methylphenyl}-1-propanol

Under an argon atmosphere,2-[(6,7-dimethoxy-4-quinolyl)oxy]-5-methylbenzaldehyde (intermediate 1)(81.6 mg) was dissolved in tetrahydrofuran (3 ml), and the solution wasthen cooled to −78° C. A 0.96 M tetrahydrofuran solution (0.4 ml) ofethylmagnesium bromide was added dropwise thereto, and the mixture wasstirred at −78° C. for 30 min. Water was added to the reaction solution,and the mixture was extracted with ethyl acetate. The ethyl acetatelayer was then washed with saturated brine and was dried over anhydroussodium sulfate. The solvent was removed therefrom by distillation underthe reduced pressure. The residue was purified by thin layerchromatography using acetone-hexane to give the title compound (41 mg,yield 46%).

¹H-NMR (CDCl₃, 400 MHz): δ 0.92 (t, J=7.3 Hz, 3H), 1.80 (m, 2H), 2.42(s, 3H), 3.99 (s, 3H), 4.02 (s, 3H), 4.75 (t, J=6.3 Hz, 1H), 6.24 (d,J=5.4 Hz, 1H), 6.95 (d, J=8.3 Hz, 1H), 7.14 (dd, J=2.2 Hz, 8.0 Hz, 1H),7.32 (s, 1H), 7.53 (s, 1H), 7.54 (d, J=1.9 Hz, 1H), 8.13 (d, J=5.4 Hz,1H)

Mass spectrometric value (ESI−MS, m/z): 354 (M+1)⁺

Compound 101-{2-[(6,7-Dimethoxy-4-quinolyl)oxy]-5-methylphenyl}-1-pentanol

Under an argon atmosphere,2-[(6,7-dimethoxy-4-quinolyl)oxy]-5-methylbenzaldehyde (123.2 mg) wasdissolved in tetrahydrofuran (3 ml), and the solution was then cooled to−78° C. A 1.56 M n-hexane solution (0.35 ml) of n-butyllithium was addeddropwise thereto, and the mixture was stirred at −78° C. for one hr. Asaturated aqueous ammonium chloride solution was added to the reactionsolution, and the mixture was extracted with ethyl acetate. The ethylacetate layer was then washed with saturated brine and was dried overanhydrous sodium sulfate. The solvent was removed therefrom bydistillation under the reduced pressure, and the residue was purified bythin layer chromatography using acetone-hexane to give the titlecompound (59.5 mg, yield 41%).

¹H-NMR (CDCl₃, 400 MHz): δ 0.81 (t, J=7.2 Hz, 3H), 1.20-1.47 (m, 4H),1.74 (m, 2H), 2.42 (s, 3H), 3.99 (s, 3H), 4.01 (s, 3H), 4.80 (dd, J=5.6Hz, 7.3 Hz, 1H), 6.20 (d, J=5.4 Hz, 1H), 6.95 (d, J=8.3 Hz, 1H), 7.13(dd, J=2.2 Hz, 8.3 Hz, 1H), 7.30 (s, 1H), 7.52 (s, 1H), 7.56 (d, J=2.0Hz, 1H), 8.06 (d, J=5.4 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 382 (M+1)⁺

Compound 111-{2-[(6,7-Dimethoxy-4-quinolyl)oxy]-5-methoxyphenyl}-1-propanol

Under an argon atmosphere,2-[(6,7-dimethoxy-4-quinolyl)oxy]-5-methoxybenzaldehyde (140 mg) wasdissolved in tetrahydrofuran (2 ml), and the solution was then cooled to−78° C. A 0.96 M tetrahydrofuran solution (0.7 ml) of ethylmagnesiumbromide was added dropwise thereto, and the mixture was stirred at −78°C. for one hr. A saturated aqueous ammonium chloride solution was addedto the reaction solution, and the mixture was extracted with ethylacetate. The ethyl acetate layer was then washed with saturated brineand was dried over anhydrous magnesium sulfate. The solvent was removedtherefrom by distillation under the reduced pressure, and the residuewas purified by thin layer chromatography using acetone-hexane to givethe title compound (74.5 mg, yield 49%).

¹H-NMR (CDCl₃, 400 MHz): δ 0.90 (t, J=7.3 Hz, 3H), 1.78 (m, 2H), 3.87(s, 3H), 4.05 (s, 6H), 4.77 (t, J=6.1 Hz, 1H), 6.35 (d, J=5.4 Hz, 1H),6.89 (dd, J=3.2 Hz, 8.8 Hz, 1H), 7.03 (d, J=8.8 Hz, 1H), 7.20 (d, J=3.2Hz, 1H), 7.42 (s, 1H), 7.55 (s, 1H), 8.39 (d, J=5.4 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 370 (M+1)⁺

Compound 12 5-{2-[6,7-Dimethoxy-4-quinolyl]oxy}-5-methylphenyl}isoxazole

4-Chloro-6,7-dimethoxyquinoline (50 mg) and2-(5-isoxazoyl)-4-methylphenol (200 mg) were dissolved inN,N-dimethylformamide (2 ml) to prepare a solution which was thenstirred at 160° C. for 4 hr. The reaction solution was cooled to roomtemperature. Water was added thereto, and the mixture was extracted withethyl acetate. The ethyl acetate layer was then washed with water andsaturated brine and was dried over anhydrous sodium sulfate. The solventwas removed therefrom by distillation under the reduced pressure, andthe residue was purified by thin layer chromatography usingacetone-chloroform to give the title compound (12 mg, yield 15%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.42 (s, 3H), 3.98 (s, 3H), 3.99 (s, 3H),6.32 (d, J=5.1 Hz, 1H), 6.40 (m, 1H), 7.04 (d, J=8.5 Hz, 1H), 7.26 (m,1H), 7.38 (s, 1H), 7.51 (s, 1H), 7.90 (d, J=1.7 Hz, 1H), 8.07 (m, 1H),8.38 (d, J=5.4 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 363 (M+1)⁺

Compound 13 6,7-Dimethoxy-4-(4-methyl-2-nitrophenoxy)quinoline

4-Chloro-6,7-dimethoxyquinoline (1.15 g) and 4-methyl-2-nitrophenol(1.52 g) were suspended in o-dichlorobenzene (7 ml), and the suspensionwas stirred at 180° C. for 23 hr. The reaction solution was cooled toroom temperature. Water was added to the reaction solution, and themixture was extracted with ethyl acetate. The ethyl acetate layer wasthen washed with water and saturated brine and was dried over anhydroussodium sulfate. The solvent was removed therefrom by distillation underthe reduced pressure, and the residue was purified by columnchromatography using acetone-chloroform to give the title compound (480mg, yield 27%).

Mass spectrometric value (ESI−MS, m/z): 341 (M+1)⁺

Compound 14N-[2-[(6,7-Dimethoxy-4-quinolyl)oxy]-5-methylphenyl]-N-phenylamine

6,7-Dimethoxy-4-(4-methyl-2-nitrophenoxy)quinoline (480 mg) wasdissolved in triethylamine/N,N-dimethylformamide (2 ml/10 ml), andpalladium hydroxide (1.2 g) was added to the solution. The mixture wasstirred at room temperature in a hydrogen gas atmosphere overnight. Thereaction solution was filtered through Celite, and the solvent wasremoved therefrom by distillation under the reduced pressure. Water wasadded to the residue, and the mixture was extracted with ethyl acetate.The ethyl acetate layer was then washed with water and saturated brineand was dried over anhydrous sodium sulfate. The solvent was removedtherefrom by distillation under the reduced pressure, and the residuewas purified by column chromatography using acetone-chloroform to give4-(2-amino-4-methylphenoxy)-6,7-dimethoxyquinoline (240 mg, yield 55%).

4-(2-Amino-4-methylphenoxy)-6,7-dimethoxyquinoline (52 mg) was dissolvedin triethylamine/N,N-dimethylformamide (0.5 ml/2.5 ml), andphenylboronic acid (100 mg) and copper acetate (250 mg) were added tothe solution which was then stirred at room temperature overnight. Thereaction solution was filtered, and the solvent was removed therefrom bydistillation under the reduced pressure. Water was added to the residue,and the mixture was extracted with ethyl acetate. Next, the ethylacetate layer was then washed with water and saturated brine and wasdried over anhydrous sodium sulfate. The solvent was removed therefromby distillation under the reduced pressure, and the residue was purifiedby thin layer chromatography using acetone-chloroform to give the titlecompound (50 mg, yield 76%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.35 (s, 3H), 4.03 (s, 3H), 4.04 (s, 3H),5.77 (s, 1H), 6.51 (d, J=5.4 Hz, 1H), 6.76 (m, 1H), 6.96 (m, 1H), 7.01(d, J=8.1 Hz, 1H), 7.05 (m, 2H), 7.23-7.27 (m, 3H), 7.43 (s, 1H), 7.54(s, 1H), 8.46 (d, J=5.1 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 387 (M+1)⁺

Compound 15 6,7-Dimethoxy-4-(3,4-dimethylphenoxy)quinoline hydrochloride

4-Chloro-6,7-dimethoxyquinoline (200 mg) and 3,4-dimethylphenol (274 mg)were suspended in diethylene glycol dimethyl ether (0.1 ml), and thesuspension was stirred at 180° C. for 1.5 hr. The reaction solution wascooled to room temperature, an aqueous sodium hydroxide solution wasadded to the reaction solution, and the mixture was extracted withchloroform. The chloroform layer was then washed with saturated brineand was dried over anhydrous sodium sulfate. The solvent was removedtherefrom by distillation under the reduced pressure, and the residuewas purified by column chromatography on silica gel usingacetone-chloroform to give6,7-dimethoxy-4-(3,4-dimethylphenoxy)quinoline (160 mg, yield 58%).

6,7-Dimethoxy-4-(3,4-dimethylphenoxy)quinoline (122 mg) was dissolved ina 10% hydrochloric acid/methanol solution, and the solution was stirredat room temperature for 15 min. The solvent was removed therefrom bydistillation under the reduced pressure. The residue was washed withethyl acetate to give the title compound (118 mg, yield 87%).

¹H-NMR (CD₃OD, 400 MHz): δ 2.30 (s, 3H), 2.30 (s, 3H), 4.03 (s, 3H),4.04 (s, 3H), 6.80 (d, J=6.6 Hz, 1H), 7.12 (dd, J=2.5 Hz, 8.3 Hz, 1H),7.20 (d, J=2.2 Hz, 1H), 7.37 (d, J=8.3 Hz, 1H), 7.64 (s, 1H), 7.72 (s,1H), 8.77 (d, J=6.6 Hz, 1H)

Compound 16 6,7-Dimethoxy-4-(1-naphthyloxy)quinoline

4-Chloro-6,7-dimethoxyquinoline (100 mg), 1-hydroxy-2-naphthonic acid(252 mg), and 4-dimethylaminopyridine (164 mg) were suspended ino-dichlorobenzene (3 ml), and the suspension was stirred at 150° C. for2 hr. The reaction solution was cooled to room temperature, water wasthen added thereto, and the mixture was extracted with ethyl acetate.The ethyl acetate layer was then washed with water and saturated brineand was dried over anhydrous sodium sulfate. The solvent was removedtherefrom by distillation under the reduced pressure, and the residuewas purified by column chromatography using acetone-chloroform to givethe title compound (119 mg, yield 80%).

¹H-NMR (CDCl₃, 400 MHz): δ 3.96 (s, 6H), 6.22 (d, J=5.2 Hz, 1H), 7.22(m, 1H), 7.31-7.40 (m, 4H), 7.64 (s, 1H), 7.68 (d, J=8.0 Hz, 1H), 7.82(t, J=8.0 Hz, 2H), 8.31 (d, J=5.2 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 332 (M+1)⁺

Compound 17 6,7-Dimethoxy-4-(2-naphthyloxy)quinoline

4-Chloro-6,7-dimethoxyquinoline (100 mg), 2-hydroxy-1-naphthonic acid(252 mg), and 4-dimethylaminopyridine (164 mg) were suspended ino-dichlorobenzene (3 ml), and the suspension was stirred at 150° C. for2 hr. The reaction solution was cooled to room temperature, water wasthen added to the reaction solution, and the mixture was extracted withethyl acetate. The ethyl acetate layer was then washed with water andsaturated brine and was dried over anhydrous sodium sulfate. The solventwas removed therefrom by distillation under the reduced pressure, andthe residue was purified by column chromatography usingacetone-chloroform to give the title compound (41 mg, yield 28%).

¹H-NMR (DMSO-d₆, 400 MHz): δ 3.99 (s, 3H), 4.02 (s, 3H), 6.62 (d, J=5.2Hz, 1H), 7.49-7.54 (m, 2H), 7.58-7.64 (m, 3H), 7.85 (s, 1H), 7.99 (d,J=7.2 Hz, 1H), 7.07 (d, J=7.2 Hz, 1H), 8.15 (d, J=9.2 Hz, 1H), 8.55 (d,J=5.2 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 332 (M+1)⁺

Compound 18 4-[(6-Bromo-2-naphthyl)oxy]-6,7-dimethoxyquinoline

4-Chloro-6,7-dimethoxyquinoline (223 mg), 1,6-dibromo-2-naphthol (910mg), and 4-dimethylaminopyridine (366 mg) were suspended ino-dichlorobenzene (3 ml), and the suspension was stirred at 150° C. for4 hr. The reaction solution was cooled to room temperature, water wasthen added to the reaction solution, and the mixture was extracted withethyl acetate. The ethyl acetate layer was then washed with water andsaturated brine and was dried over anhydrous sodium sulfate. The solventwas removed therefrom by distillation under the reduced pressure, andthe residue was purified by column chromatography usingacetone-chloroform to give4-[(1,6-dibromo-2-naphthyl)oxy]-6,7-dimethoxyquinoline (326 mg, yield67%).

4-[(1,6-Dibromo-2-naphthyl)oxy]-6,7-dimethoxyquinoline (65 mg) wasdissolved in tetrahydrofuran (3 ml) to prepare a solution which was thencooled to −78° C. A 1.59 M n-butyllithium/hexane solution (0.4 ml) wasadded thereto, and the mixture was stirred at −78° C. for 20 min. Acetylchloride (0.2 ml) was added to the reaction solution, and the mixturewas stirred at room temperature overnight. Further, water was added tothe reaction solution, and the mixture was extracted with ethyl acetate.The ethyl acetate layer was then washed with water and saturated brineand dried over anhydrous sodium sulfate. The solvent was removedtherefrom by distillation under the reduced pressure, and the residuewas purified by thin layer chromatography using acetone-chloroform togive the title compound (28 mg, yield 51%).

¹H-NMR (CDCl₃, 400 MHz): δ 4.05 (s, 3H), 4.06 (s, 3H), 6.52 (d, J=5.4Hz, 1H), 7.27 (s, 1H), 7.50-7.97 (m, 6H), 8.06 (m, 1H), 8.53 (d, J=5.1Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 410 (M+1)⁺

Compound 19 2-[(6,7-Dimethoxy-4-quinolyl)oxy]fluoren-9-one

4-Chloro-6,7-dimethoxyquinoline (100 mg), 2-hydroxy-9-fluorenone (269mg), and 4-dimethylaminopyridine (164 mg) were suspended ino-dichlorobenzene (6 ml), and the suspension was stirred at 160° C. for7 hr. The reaction solution was cooled to room temperature, water wasthen added to the reaction solution, and the mixture was extracted withethyl acetate. The ethyl acetate layer was then washed with water andsaturated brine and was dried over anhydrous sodium sulfate. The solventwas removed therefrom by distillation under the reduced pressure, andthe residue was purified by column chromatography usingacetone-chloroform to give the title compound (58 mg, yield 34%).

¹H-NMR (CDCl₃, 400 MHz): δ 4.03 (s, 3H), 4.04 (s, 3H), 6.56 (d, J=5.2Hz, 1H), 7.27-7.29 (m, 2H), 7.44-7.67 (m, 7H), 8.51 (d, J=5.2 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 384 (M+1)⁺

Compound 20 6,7-Dimethoxy-4-[(1-methyl-5-indolyl)oxy]quinoline

A mixture of 4-chloro-6,7-dimethoxyquinoline (1 g) with5-hydroroxyindole (1.19 g) was stirred at 150° C. for 1.5 hr and wascooled to room temperature. Water was then added to the reactionsolution, and the mixture was extracted with ethyl acetate. The ethylacetate layer was then washed with an aqueous sodium hydrogencarbonatesolution and saturated brine and was dried over anhydrous sodiumsulfate. The solvent was removed therefrom by distillation under thereduced pressure, and the residue was purified by column chromatographyusing ethyl acetate-hexane to give6,7-dimethoxy-4-[(1H-5-indolyl)oxy]quinoline (898 mg, yield 63%).

6,7-Dimethoxy-4-[(1H-5-indolyl)oxy]quinoline (50 mg) was dissolved inN,N-dimethylformamide (1 ml), and 60% sodium hydride (7 mg) was added,followed by stirring for 30 min under ice cooling. Methyl iodide (0.0107ml) was added to the reaction solution, and the mixture was stirredunder ice cooling for additional one hr. Water was added to the reactionsolution, and the mixture was extracted with ethyl acetate. The ethylacetate layer was then washed with water and saturated brine and wasdried over anhydrous sodium sulfate. The solvent was removed therefromby distillation under the reduced pressure, and the residue was purifiedby thin layer chromatography using methanol-chloroform to give the titlecompound (32 mg, yield 62%).

¹H-NMR (CDCl₃, 500 MHz): δ 3.86 (s, 3H), 4.06 (s, 3H), 4.08 (s, 3H),6.39 (d, J=5.5 Hz, 1H), 6.50 (d, J=3.1 Hz, 1H), 7.06 (dd, J=2.4 Hz, 8.6Hz, 1H), 7.15 (d, J=3.1 Hz, 1H), 7.39 (d, J=8.5 Hz, 1H), 7.43 (s, 1H),7.43 (d, J=2.4 Hz, 1H), 7.6, 7 (s, 1H), 8.43 (d, J=5.5 Hz, 1H)

Mass spectrometric value (FD−MS, m/z): 334 (M⁺)

Compound 21 6,7-Dimethoxy-4-[(1-acetyl-5-indolyl)oxy]quinoline

6,7-Dimethoxy-4-[(1H-5-indolyl)oxy]quinoline (50 mg) was dissolved inN,N-dimethylformamide (1 ml), and 60% sodium hydride (7 mg) was added tothe solution, followed by stirring under ice cooling for 30 min. Acetylchloride (16.6 μl) was added to the reaction solution, and the mixturewas stirred under ice cooling for additional one hr. Further, water wasadded to the reaction solution, and the mixture was extracted with ethylacetate. The ethyl acetate layer was then washed with water andsaturated brine and was dried over anhydrous sodium sulfate. The solventwas removed therefrom by distillation under the reduced pressure, andthe residue was purified by thin layer chromatography usingmethanol-chloroform to give the title compound (23 mg, yield 41%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.68 (s, 3H), 4.06 (s, 3H), 4.06 (s, 3H),6.43 (d, J=5.5 Hz, 1H), 6.66 (d, J=4.3 Hz, 1H), 7.20 (dd, J=2.4 Hz, 8.6Hz, 1H), 7.37 (d, J=2.5 Hz, 1H), 7.44 (s, 1H), 7.51 (d, J=3.7 Hz, 1H),7.62 (s, 1H), 8.47 (d, J=5.5 Hz, 1H), 8.55 (d, J=9.2 Hz, 1H)

Mass spectrometric value (FD−MS, m/z): 362 (M⁺)

Compound 22 Ethyl5-[(6,7-dimethoxy-4-quinolyl)oxy]-1H-2-indolecarboxylate

5-Hydroxy-1H-2-indolecarboxylic acid (328 mg) was dissolved in ethanol(10 ml) to prepare a solution. Concentrated sulfuric acid was added tothe solution, and the mixture was heated under reflux for 3 hr. Thereaction solution was cooled to room temperature, an aqueous sodiumhydrogencarbonate solution was then added thereto, and the mixture wasextracted with ethyl acetate. The ethyl acetate layer was then washedwith saturated brine and was dried over anhydrous magnesium sulfate. Thesolvent was removed therefrom by distillation under the reducedpressure, and the residue was purified by column chromatography onsilica gel using ethyl acetate-hexane to give ethyl5-hydroxy-1H-2-indolecarboxylate (336 mg, yield 88%).

4-Chloro-6,7-dimethoxyquinoline (362 mg), ethyl5-hydroxy-1H-2-indolecarboxylate (277 mg), and 4-dimethylaminopyridine(195 mg) were suspended in o-xylene, and the suspension was heated underreflux overnight. The reaction solution was cooled to room temperature,water was then added to the reaction solution, and the mixture wasextracted with ethyl acetate. The ethyl acetate layer was then washedwith saturated brine and was dried over anhydrous magnesium sulfate. Thesolvent was removed therefrom by distillation under the reducedpressure, and the residue was purified by column chromatography usingethyl acetate-hexane on silica gel to give the title compound (161 mg,yield 30%).

¹H-NMR (CDCl₃, 400 MHz): δ 1.43 (t, J=7.1 Hz, 3H), 4.07 (s, 3H), 4.07(s, 3H), 4.44 (q, J=7.1 Hz, 2H), 6.43 (d, J=5.4 Hz, 1H), 7.18 (dd, J=2.2Hz, 9.0 Hz, 1H), 7.24 (m, 1H), 7.47 (s, 1H), 7.50-7.52 (m, 2H), 7.64 (s,1H), 8.46 (d, J=5.4 Hz, 1H), 9.05 (s, 1H)

Mass spectrometric value (ESI−MS, m/z): 393 (M+1)⁺

Compound 236-[(6,7-Dimethoxy-4-quinolyl)oxy]-1,4-dihydro-2H-3,1-benzoxazin-2-one

4-Chloro-6,7-dimethoxyquinoline (200 mg) and5-hydroxy-2-nitrobenzaldehyde (299 mg) were suspended in chlorobenzene(2 ml), and the suspension was heated under reflux for 8 hr. Thereaction solution was cooled to room temperature, water was then addedto the reaction solution, and the mixture was extracted with ethylacetate. The ethyl acetate layer was then washed with water andsaturated brine and was dried over anhydrous sodium sulfate. The solventwas removed therefrom by distillation under the reduced pressure, andthe residue was purified by thin layer chromatography using ethylacetate-hexane to give3-[(6,7-dimethoxy-4-quinolyl)oxy]-6-nitrobenzaldehyde (210 mg, yield66%).

3-[(6,7-Dimethoxy-4-quinolyl)oxy]-6-nitrobenzaldehyde (201 mg) wasdissolved in chloroform/methanol (5 ml/10 ml), and sodium borohydride(127 mg) was added to the solution under ice cooling. The mixture wasstirred at room temperature for one hr, water was then added to thereaction solution, and the mixture was extracted with ethyl acetate. Theethyl acetate layer was then washed with water and saturated brine andwas dried over anhydrous sodium sulfate. The solvent was removedtherefrom by distillation under the reduced pressure, and the residuewas used in the next reaction without purification.

The residue was dissolved in ethyl acetate/N,N-dimethylformamide (5 ml/5ml) to prepare a solution. Triethylamine (4 ml) and 20% palladiumhydroxide (0.9 g) were added to the solution, and the mixture wasstirred under a hydrogen gas atmosphere at room temperature overnight.The reaction solution was filtered through Celite, and the solvent wasremoved by distillation under the reduced pressure. Water was added tothe residue, and the mixture was extracted with ethyl acetate. The ethylacetate layer was then washed with water and saturated brine and wasdried over anhydrous sodium sulfate. The solvent was removed therefromby distillation under the reduced pressure. The residue was purified bycolumn chromatography on silica gel using acetone-chloroform to give{2-amino-5-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}methanol (118 mg, yield64%) (2 steps).

{2-Amino-5-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}methanol (63 mg) wasdissolved in heated triethylamine/toluene (1.2 ml/6 ml) to prepare asolution. Triphosgene (98 mg) was added to the solution and was heatedunder reflux for 2 min. The reaction solution was cooled to roomtemperature, water was then added to the reaction solution, and themixture was extracted with chloroform. The chloroform layer was thenwashed with water and saturated brine and was dried over anhydroussodium sulfate. The solvent was removed therefrom by distillation underthe reduced pressure, and the residue was purified by columnchromatography on silica gel using acetone-chloroform to give the titlecompound (24 mg, yield 39%).

¹H-NMR (CDCl₃, 500 MHz): δ 4.06 (s, 3H), 4.09 (s, 3H), 5.36 (s, 2H),6.47 (d, J=5.1 Hz, 1H), 7.00 (s, 1H), 7.04 (d, J=8.5 Hz, 1H), 7.14 (d,J=8.3 Hz, 1H), 7.52 (s, 1H), 7.53 (s, 1H), 8.53 (m, 1H), 9.13 (s, 1H)

Mass spectrometric value (FD−MS, m/z): 352 (M⁺)

Compound 24 6,7-Dimethoxy-4-(6-quinolyloxy)quinoline

A mixture of 4-chloro-6,7-dimethoxyquinoline (90 mg) with6-hydroxyquinoline (176 mg) was stirred at 180° C. for 30 min. Thereaction solution was cooled to room temperature, and was then purifiedby column chromatography on silica gel using acetone-hexane to give thetitle compound (62 mg, yield 46%).

¹H-NMR (CDCl₃, 500 MHz): δ 4.05 (s, 3H), 4.06 (s, 3H), 6.50 (d, J=5.5Hz, 1H), 7.44-7.62 (m, 5H), 8.13 (d, J=8.5 Hz, 1H), 8.23 (d, J=9.2 Hz,1H), 8.53 (d, J=4.9 Hz, 1H), 8.94 (d, J=4.3 Hz, 1H)

Mass spectrometric value (FD−MS, m/z): 332 (M⁺)

Compound 26 2-[(6,7-Dimethoxy-4-quinolyl)oxy]-5-methoxybenzaldehyde

4-Chloro-6,7-dimethoxyquinoline (115 mg),2-hydroxy-5-methoxybenzaldehyde (385 mg), and 4-dimethylaminopyridine(321 mg) were suspended in o-dichlorobenzene (5 ml), and the suspensionwas stirred at 160° C. for 4 hr. The reaction solution was cooled toroom temperature, and the solvent was then removed therefrom bydistillation under the reduced pressure. Chloroform was added to theresidue, and the organic layer was washed with a 1 N aqueous potassiumhydroxide solution and saturated brine and was dried over anhydroussodium sulfate. The solvent was removed therefrom by distillation underthe reduced pressure, and the residue was purified by columnchromatography using chloroform and by thin layer chromatography usingacetone-hexane to quantitatively obtain 180 mg of the title compound.

¹H-NMR (CDCl₃, 400 MHz): δ 3.91 (s, 3H), 4.07 (s, 3H), 4.07 (s, 3H),6.39 (d, J=5.1 Hz, 1H), 7.16 (d, J=9.0 Hz, 1H), 7.25 (d, J=3.2 Hz, 1H),7.45 (s, 1H), 7.49 (d, J=2.9 Hz, 1H), 7.59 (s, 1H), 8.50 (d, J=5.1 Hz,1H), 10.23 (s, 1H)

Mass spectrometric value (ESI−MS, m/z): 340 (M+1)⁺

Compound 27 2-[(6,7-Dimethoxy-4-quinolyl)oxy]naphthalene-1-carbaldehyde

4-Chloro-6,7-dimethoxyquinoline (100 mg), 2-hydroxy-1-naphthoaldehyde(231 mg), and 4-dimethylaminopyridine (164 mg) were suspended ino-dichlorobenzene (6 ml), and the suspension was stirred at 160° C. for2 hr. The reaction solution was cooled to room temperature, water wasthen added to the reaction solution, and the mixture was extracted withethyl acetate. The ethyl acetate layer was then washed with water andsaturated brine and was dried over anhydrous sodium sulfate. The solventwas removed therefrom by distillation under the reduced pressure, andthe residue was purified by column chromatography usingacetone-chloroform to give the title compound (24 mg, yield 15%).

¹H-NMR (CDCl₃, 400 MHz): δ 3.99 (s, 6H), 6.43 (d, J=5.2 Hz, 1H), 7.19(m, 1H), 7.42 (s, 1H), 7.51-7.55 (m, 2H), 7.66 (t, J=8.0 Hz, 1H), 7.83(d, J=8.4 Hz, 1H), 8.07 (d, J=8.4 Hz, 1H), 8.45 (d, J=5.2 Hz, 1H), 9.25(d, J=8.0 Hz, 1H), 10.73 (s, 1H)

Mass spectrometric value (ESI−MS, m/z): 360 (M+1)⁺

Compound 289-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,3,6,7-tetrahydro-1H,5H-pyrido[3,2,1-ij]quinoline-8-carbaldehyde

4-Chloro-6,7-dimethoxyquinoline (100 mg), 8-hydroxydurolysine-9-aldehyde(291 mg) and 4-dimethylaminopyridine (164 mg) were suspended ino-dichlorobenzene (6 ml), and the suspension was stirred at 120° C. for48 hr. The reaction solution was cooled to room temperature, water wasthen added to the reaction solution, and the mixture was extracted withethyl acetate. The ethyl acetate layer was then washed with water andsaturated brine and was dried over anhydrous sodium sulfate. The solventwas removed therefrom by distillation under the reduced pressure, andthe residue was purified by column chromatography using acetone-hexaneto give the title compound (7 mg, yield 4%).

¹H-NMR (CDCl₃, 400 MHz): δ 1.75-1.81 (m, 2H), 1.90-1.96 (m, 2H),2.12-2.21 (m, 1H), 2.63-2.73 (m, 3H), 3.19-3.27 (m, 4H), 3.98 (s, 3H),4.01 (s, 3H), 6.27 (d, J=5.2 Hz, 1H), 7.42 (m, 2H), 7.55 (s, 1H), 8.37(d, J=5.2 Hz, 1H), 9.69 (s, 1H)

Mass spectrometric value (ESI−MS, m/z): 405 (M+1)⁺

Compound 29 1-{2-[(6,7-Dimethoxy-4-quinolyl)oxy]phenyl}-1-ethanone

4-Chloro-6,7-dimethoxyquinoline (58.1 mg), 2′-hydroxyacetophenone (361mg), and 4-dimethylaminopyridine (317 mg) were suspended ino-dichlorobenzene (5 ml), and the suspension was stirred at 160° C. for11 hr. The reaction solution was cooled to room temperature, and thesolvent was then removed therefrom by distillation under the reducedpressure. Chloroform was added to the residue. The organic layer waswashed with a 1 N aqueous potassium hydroxide solution and saturatedbrine and was dried over anhydrous sodium sulfate. The solvent wasremoved therefrom by distillation under the reduced pressure, and theresidue was purified by column chromatography using chloroform and bythin layer chromatography using acetone-hexane to give the titlecompound (36 mg, yield 43%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.54 (s, 3H), 4.05 (s, 3H), 4.06 (s, 3H),6.45 (d, J=5.1 Hz, 1H), 7.16 (dd, J=1.0 Hz, 8.1 Hz, 1H), 7.38 (m, 1H),7.46 (s, 1H), 7.55 (s, 1H), 7.59 (m, 1H), 7.94 (dd, J=1.7 Hz, 7.8 Hz,1H), 8.52 (d, J=5.4 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 324 (M+1)⁺

Compound 301-{2-[(6,7-Dimethoxy-4-quinolyl)oxy]-3-methoxyphenyl}-1-ethanone

4-Chloro-6,7-dimethoxyquinoline (100 mg),2-hydroxy-3-methoxyacetophenone (223 mg), and 4-dimethylaminopyridine(164 mg) were suspended in o-dichlorobenzene (6 ml), and the suspensionwas stirred at 150° C. for 2 hr. The reaction solution was cooled toroom temperature, water was then added to the reaction solution, and themixture was extracted with ethyl acetate. The ethyl acetate layer wasthen washed with water and saturated brine and was dried over anhydroussodium sulfate. The solvent was removed therefrom by distillation underthe reduced pressure, and the residue was purified by columnchromatography using acetone-chloroform to give the title compound (46mg, yield 28%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.41 (s, 3H), 3.85 (s, 3H), 3.98 (s, 3H),3.99 (s, 3H), 6.52 (d, J=5.2 Hz, 1H), 6.67 (d, J=8.2 Hz, 1H), 6.80 (d,J=8.2 Hz, 1H), 7.33 (t, J=8.2 Hz, 1H), 7.38 (s, 1H), 7.43 (s, 1H), 8.47(d, J=5.2 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 354 (M+1)⁺

Compound 311-{2-[(6,7-Dimethoxy-4-quinolyl)oxy]-4-methoxyphenyl}-1-ethanone

4-Chloro-6,7-dimethoxyquinoline (112 mg),2-hydroxy-4-methoxyacetophenone (873 mg), and 4-dimethylaminopyridine(619 mg) were suspended in o-dichlorobenzene (5 ml), and the suspensionwas stirred at 160° C. for 7 hr. The reaction solution was cooled toroom temperature, and the solvent was then removed therefrom bydistillation under the reduced pressure. Chloroform was added to theresidue, and the organic layer was washed with a 1 N aqueous potassiumhydroxide solution and saturated brine and was dried over anhydroussodium sulfate. The solvent was removed therefrom by distillation underthe reduced pressure, and the residue was purified by columnchromatography using chloroform and by thin layer chromatography usingacetone-hexane to give the title compound (53.9 mg, yield 31%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.50 (s, 3H), 3.83 (s, 3H), 4.05 (s, 3H),4.06 (s, 3H), 6.49 (d, J=5.4 Hz, 1H), 6.62 (d, J=2.4 Hz, 1H), 6.89 (dd,J=2.4 Hz, 8.8 Hz, 1H), 7.46 (s, 1H), 7.55 (s, 1H), 8.00 (d, J=8.8 Hz,1H), 8.53 (d, J=5.1 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 354 (M+1)⁺

Compound 321-{2-[(6,7-Dimethoxy-4-quinolyl)oxy]-4-methylphenyl}-1-ethanone

4-Chloro-6,7-dimethoxyquinoline (116 mg), 2-hydroxy-4-methylacetophenone(300 mg), and 4-dimethylaminopyridine (244 mg) were suspended ino-dichlorobenzene (1 ml), and the suspension was stirred at 120° C.overnight. The reaction solution was cooled to room temperature, and thesolvent was removed by distillation under the reduced pressure. Waterwas then added to the residue, and the mixture was extracted withchloroform. The chloroform layer was washed with water and was driedover anhydrous sodium sulfate. The solvent was removed therefrom bydistillation under the reduced pressure, and the residue was purified bycolumn chromatography using acetone-hexane to give the title compound(37 mg, yield 6%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.40 (s, 3H), 2.51 (s, 3H), 4.05 (s, 3H),4.06 (s, 3H), 6.44 (d, J=5.1 Hz, 1H), 6.95 (s, 1H), 7.17 (d, J=8.1 Hz,1H), 7.45 (s, 1H), 7.55 (s, 1H), 7.87 (d, J=8.1 Hz, 1H), 8.52 (d, J=5.1Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 338 (M+1)⁺

Compound 331-{2-[(6,7-Dimethoxy-4-quinolyl)oxy]-5-fluorophenyl}-1-ethanone

4-Chloro-6,7-dimethoxyquinoline (58.2 mg),5-fluoro-2-hydroxyacetophenone (409 mg), and 4-dimethylaminopyridine(317 mg) were suspended in o-dichlorobenzene (5 ml), and the suspensionwas stirred at 160° C. for 8 hr. The reaction solution was cooled toroom temperature, and the solvent was then removed therefrom bydistillation under the reduced pressure. Chloroform was added to theresidue, and the organic layer was washed with a 1 N aqueous potassiumhydroxide solution and saturated brine and was dried over anhydroussodium sulfate. The solvent was removed therefrom by distillation underthe reduced pressure, and the residue was purified by columnchromatography using chloroform and by thin layer chromatography usingacetone-hexane to give the title compound (63.5 mg, yield 72%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.53 (s, 3H), 4.06 (s, 3H), 4.06 (s, 3H),6.41 (d, J=5.1 Hz, 1H), 7.17 (dd, J=4.4 Hz, 9.0 Hz, 1H), 7.30 (m, 1H),7.46 (s, 1H), 7.55 (s, 1H), 7.64 (dd, J=3.2 Hz, 8.8 Hz, 1H), 8.53 (d,J=5.1 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 342 (M+1)⁺

Compound 341-{5-Bromo-2-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}-1-ethanone

4-Chloro-6,7-dimethoxyquinoline (113 mg), 5-bromo-2-hydroxyacetophenone(550 mg), and 4-dimethylaminopyridine (311 mg) were suspended ino-dichlorobenzene (5 ml), and the suspension was stirred at 160° C. for4 hr. The reaction solution was cooled to room temperature, and thesolvent was then removed therefrom by distillation under the reducedpressure. Chloroform was added to the residue, and the organic layer waswashed with a 1 N aqueous potassium hydroxide solution and saturatedbrine and was dried over anhydrous sodium sulfate. The solvent wasremoved therefrom by distillation under the reduced pressure, and theresidue was purified by column chromatography using chloroform and bythin layer chromatography using acetone-hexane to give the titlecompound (96.2 mg, yield 47%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.54 (s, 3H), 4.05 (s, 3H), 4.06 (s, 3H),6.47 (d, J=5.4 Hz, 1H), 7.05 (d, J=8.6 Hz, 1H), 7.46 (s, 1H), 7.51 (s,1H), 7.68 (dd, J=2.7 Hz, 8.6 Hz, 1H), 8.05 (d, J=2.7 Hz, 1H), 8.54 (d,J=5.1 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 402 (M+1)⁺

Compound 351-{2-[(6,7-Dimethoxy-4-quinolyl)oxy]-5-methylphenyl}-1-ethanone

4-Chloro-6,7-dimethoxyquinoline (220 mg) and 2-acetyl-4-methylphenol(300 mg) were suspended in o-dichlorobenzene (2 ml), and the suspensionwas stirred at 170° C. for 6 days. The reaction solution was cooled toroom temperature, water was then added to the reaction solution, and themixture was extracted with ethyl acetate. The ethyl acetate layer wasthen washed with water and saturated brine and was dried over anhydroussodium sulfate. The solvent was removed therefrom by distillation underthe reduced pressure, and the residue was purified by thin layerchromatography using acetone-chloroform to give the title compound (12mg, yield 4%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.37 (s, 3H), 2.43 (s, 3H), 3.98 (s, 3H),3.99 (s, 3H), 6.34 (d, J=5.1 Hz, 1H), 6.98 (d, J=8.3 Hz, 1H), 7.32 (dd,J=2.0 Hz, 8.3 Hz, 1H), 7.38 (s, 1H), 7.48 (s, 1H), 7.66 (d, J=2.0 Hz,1H), 8.42 (d, J=5.4 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 338 (M+1)⁺

Compound 361-{2-[(6,7-Dimethoxy-4-quinolyl)oxy]-5-methoxyphenyl}-1-ethanone

4-Chloro-6,7-dimethoxyquinoline (59.4 mg),2-hydroxy-5-methoxyacetophenone (436 mg), and 4-dimethylaminopyridine(328 mg) were suspended in o-dichlorobenzene (5 ml), and the suspensionwas stirred at 160° C. for 6 hr. The reaction solution was cooled toroom temperature, and the solvent was then removed therefrom bydistillation under the reduced pressure. Chloroform was added to theresidue, and the organic layer was washed with a 1 N aqueous potassiumhydroxide solution and saturated brine and was dried over anhydroussodium sulfate. The solvent was removed therefrom by distillation underthe reduced pressure, and the residue was purified by columnchromatography using chloroform and by thin layer chromatography usingacetone-hexane to give the title compound (68.6 mg, yield 73%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.50 (s, 3H), 3.89 (s, 3H), 4.06 (s, 6H),6.38 (d, J=5.1 Hz, 1H), 7.11 (d, J=8.8 Hz, 1H), 7.15 (dd, J=2.9 Hz, 8.8Hz, 1H), 7.43 (d, J=3.0 Hz, 1H), 7.45 (s, 1H), 7.58 (s, 1H), 8.50 (d,J=5.4 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 354 (M+1)⁺

Compound 371-{5-Chloro-2-[(6,7-dimethoxy-4-quinolyl)oxy]-4-methylphenyl}-1-ethanone

4-Chloro-6,7-dimethoxyquinoline (100 mg),5-chloro-2-hydroxy-4-methylacetophenone (248 mg), and4-dimethylaminopyridine (164 mg) were suspended in o-dichlorobenzene (6ml), and the suspension was stirred at 150° C. for 2 hr. The reactionsolution was cooled to room temperature, water was then added to thereaction solution, and the mixture was extracted with ethyl acetate. Theethyl acetate layer was then washed with water and saturated brine andwas dried over anhydrous sodium sulfate. The solvent was removedtherefrom by distillation under the reduced pressure, and the residuewas purified by column chromatography using acetone-chloroform to givethe title compound (71 mg, yield 45%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.32 (s, 3H), 2.42 (s, 3H), 3.97 (s, 6H),6.39 (d, J=5.2 Hz, 1H), 6.99 (s, 1H), 7.43 (s, 1H), 7.47 (s, 1H), 7.83(s, 1H), 8.41 (d, J=5.2 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 372 (M+1)⁺

Compound 381-{2-[(6,7-Dimethoxy-4-quinolyl)oxy]-4,5-dimethylphenyl}-1-ethanone

4-Chloro-6,7-dimethoxyquinoline (100 mg),4,5-dimethyl-2-hydroxyacetophenone (220 mg), and 4-dimethylaminopyridine(164 mg) were suspended in o-dichlorobenzene (6 ml), and the suspensionwas stirred at 120° C. for 24 hr. The reaction solution was cooled toroom temperature, water was then added to the reaction solution, and themixture was extracted with ethyl acetate. The ethyl acetate layer wasthen washed with water and saturated brine and was dried over anhydroussodium sulfate. The solvent was removed therefrom by distillation underthe reduced pressure, and the residue was purified by columnchromatography using acetone-hexane to give the title compound (34 mg,yield 22%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.22 (s, 3H), 2.26 (s, 3H), 2.40 (s, 3H),3.97 (s, 3H), 3.98 (s, 3H), 6.33 (d, J=5.4 Hz, 1H), 6.85 (s, 1H), 7.37(s, 1H), 7.48 (s, 1H), 7.65 (s, 1H), 8.41 (d, J=5.4 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 352 (M+1)⁺

Compound 391-{4,5-Dimethoxy-2-[(6,7-dimethoxy-4-quinolyl)oxy]-phenyl}-1-ethanone

4-Chloro-6,7-dimethoxyquinoline (56 mg),2-hydroxy-4,5-dimethoxyacetophenone (196 mg), and4-dimethylaminopyridine (122 mg) were suspended in o-dichlorobenzene (1ml), and the suspension was stirred at 120° C. overnight. The reactionsolution was cooled to room temperature, and the solvent was removed bydistillation under the reduced pressure. Water was then added to theresidue, and the mixture was extracted with chloroform. The chloroformlayer was washed with water and was dried over anhydrous sodium sulfate.The solvent was removed therefrom by distillation under the reducedpressure. The residue was purified by column chromatography usingacetone-hexane to give the title compound (29 mg, yield 30%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.47 (s, 3H), 3.87 (s, 3H), 3.99 (s, 3H),4.07 (s, 6H), 6.40 (d, J=5.3 Hz, 1H), 6.62 (s, 1H), 7.46 (s, 1H), 7.54(s, 1H), 7.58 (s, 1H), 8.51 (d, J=5.3 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 384 (M+1)⁺

Compound 401-{4,6-Dimethoxy-2-[(6,7-dimethoxy-4-quinolyl)oxy]-phenyl}-1-ethanone

4-Chloro-6,7-dimethoxyquinoline (56 mg),2-hydroxy-4,6-dimethoxyacetophenone (196 mg), and4-dimethylaminopyridine (122 mg) were suspended in o-dichlorobenzene (1ml), and the suspension was stirred at 120° C. overnight. The reactionsolution was cooled to room temperature, and the solvent was removed bydistillation under the reduced pressure. Water was then added to theresidue, and the mixture was extracted with chloroform. The chloroformlayer was washed with water and was dried over anhydrous sodium sulfate.The solvent was removed therefrom by distillation under the reducedpressure. The residue was purified by column chromatography usingacetone-hexane to give the title compound (25 mg, yield 27%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.42 (s, 3H), 3.77 (s, 3H), 3.88 (s, 3H),4.04 (s, 3H), 4.04 (s, 3H), 6.23 (d, J=2.2 Hz, 1H), 6.39 (d, J=2.2 Hz,1H), 6.56 (d, J=5.1 Hz, 1H), 7.42 (s, 1H), 7.48 (s, 1H), 8.51 (d, J=5.1Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 384 (M+1)⁺

Compound 41 1-{1-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-naphthyl}-1-ethanone

4-Chloro-6,7-dimethoxyquinoline (100 mg), 1-hydroxy-2-acetonaphthone(250 mg), and 4-dimethylaminopyridine (164 mg) were suspended ino-dichlorobenzene (5 ml), and the suspension was stirred at 160° C. for2 hr. The reaction solution was cooled to room temperature, water wasthen added to the reaction solution, and the mixture was extracted withethyl acetate. The ethyl acetate layer was then washed with water andsaturated brine and was dried over anhydrous sodium sulfate. The solventwas removed therefrom by distillation under the reduced pressure, andthe residue was purified by column chromatography usingacetone-chloroform to give the title compound (5 mg, yield 3%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.51 (s, 3H), 4.03 (s, 3H), 4.05 (s, 3H),6.01 (d, J=5.2 Hz, 1H), 7.38 (t, J=8.0 Hz, 1H), 7.51-7.60 (m, 2H),7.76-7.93 (m, 5H), 8.29 (d, J=5.2 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 374 (M+1)⁺

Compound 42 1-{2-[(6,7-Dimethoxy-4-quinolyl)oxy]-1-naphthyl}-1-ethanone

4-Chloro-6,7-dimethoxyquinoline (100 mg), 2-hydroxy-1-acetonaphthone(250 mg), and 4-dimethylaminopyridine (164 mg) were suspended ino-dichlorobenzene (6 ml), and the suspension was stirred at 160° C. for2 hr. The reaction solution was cooled to room temperature, water wasthen added to the reaction solution, and the mixture was extracted withethyl acetate. The ethyl acetate layer was then washed with water andsaturated brine and was dried over anhydrous sodium sulfate. The solventwas removed therefrom by distillation under the reduced pressure, andthe residue was purified by column chromatography usingacetone-chloroform to give the title compound (100 mg, yield 60%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.53 (s, 3H), 3.94 (s, 3H), 3.95 (s, 3H),6.44 (d, J=5.2 Hz, 1H), 7.44 (d, J=8.8 Hz, 1H), 7.36-7.51 (m, 4H),7.79-7.86 (m, 3H), 8.42 (d, J=5.2 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 374 (M+1)⁺

Compound 431-{2-[(6,7-Dimethoxy-4-quinolyl)oxy]-3-fluorophenyl}-1-propanone

4-Chloro-6,7-dimethoxyquinoline (111 mg), 3-fluorosalicylaldehyde (280mg), and 4-dimethylaminopyridine (244 mg) were suspended inmonochlorobenzene (2 ml), and the suspension was stirred at 130° C.overnight. The reaction solution was cooled to room temperature, waterwas then added to the reaction solution, and the mixture was extractedwith ethyl acetate. The ethyl acetate layer was then washed with waterand saturated brine and was dried over anhydrous sodium sulfate. Thesolvent was removed therefrom by distillation under the reducedpressure, and the residue was purified by chromatography on silica gelusing ethyl acetate-hexane for development to give2-[(6,7-dimethoxy-4-quinolyl)oxy]-3-fluorobenzaldehyde.

2-[(6,7-Dimethoxy-4-quinolyl)oxy]-3-fluorobenzaldehyde was dissolved inanhydrous tetrahydrofuran (1 ml). A 1 M tetrahydrofuran solution ofethylmagnesium bromide (0.5 ml) was added thereto at 0° C., and themixture was stirred at 0° C. for one hr. Water (1 ml) was added dropwiseto the reaction solution to stop the reaction, followed by extractionwith ethyl acetate. The ethyl acetate layer was then washed with waterand saturated brine and was dried over anhydrous sodium sulfate. Thesolvent was removed by distillation under the reduced pressure to give1-{2-[(6,7-dimethoxy-4-quinolyl)oxy]-3-fluorophenyl}-1-propanol.

1-{2-[(6,7-Dimethoxy-4-quinolyl)oxy]-3-fluorophenyl}-1-propanol wasdissolved in anhydrous dimethylsulfoxide (1 ml). Sulfur trioxidetrimethylamine complex (70 mg) was added to the solution at 0° C., andthe mixture was stirred at room temperature for 18 hr. Water (1 ml) wasadded dropwise to the reaction solution to stop the reaction. Thereaction solution was extracted with ethyl acetate, and the ethylacetate layer was then washed with water and saturated brine and wasdried over anhydrous sodium sulfate. The solvent was removed therefromby distillation under the reduced pressure, and the residue was purifiedby chromatography on silica gel using ethyl acetate-hexane fordevelopment to give the title compound (2 mg, yield 1%).

¹H-NMR (CDCl₃, 400 MHz): δ 1.03 (t, J=7.2 Hz, 3H), 2.84 (q, J=7.2 Hz,2H), 4.05 (s, 6H), 6.34 (d, J=5.4 Hz, 1H), 7.32-7.42 (m, 2H), 7.45 (s,1H), 7.56 (s, 1H), 7.63-7.67 (m, 1H), 8.48 (d, J=5.4 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 356 (M+1)⁺

Compound 441-{2-[(6,7-Dimethoxy-4-quinolyl)oxy]-4-methoxyphenyl}-1-propanone

4-Chloro-6,7-dimethoxyquinoline (111 mg),2-hydroxy-4-methoxybenzaldehyde (304 mg), and 4-dimethylaminopyridine(244 mg) were suspended in monochlorobenzene (2 ml), and the suspensionwas stirred at 130° C. overnight. The reaction solution was cooled toroom temperature, water was then added to the reaction solution, and themixture was extracted with ethyl acetate. The ethyl acetate layer wasthen washed with water and saturated brine and was dried over anhydroussodium sulfate. The solvent was removed therefrom by distillation underthe reduced pressure, and the residue was purified by chromatography onsilica gel using ethyl acetate-hexane for development to give2-[(6,7-dimethoxy-4-quinolyl)oxy]-4-methoxybenzaldehyde.

2-[(6,7-Dimethoxy-4-quinolyl)oxy]-4-methoxybenzaldehyde was dissolved inanhydrous tetrahydrofuran (1 ml), and a 1 M tetrahydrofuran solution ofethylmagnesium bromide (0.5 ml) was added to the solution at 0° C., andthe mixture was stirred at 0° C. for one hr. Water (1 ml) was addeddropwise to the reaction solution to stop the reaction. The mixture wasextracted with ethyl acetate, and the ethyl acetate layer was thenwashed with water and saturated brine and was dried over anhydroussodium sulfate. The solvent was removed by distillation under thereduced pressure to give1-{2-[(6,7-dimethoxy-4-quinolyl)oxy]-4-methoxyphenyl}-1-propanol.

1-{2-[(6,7-Dimethoxy-4-quinolyl)oxy]-4-methoxyphenyl}-1-propanol wasdissolved in anhydrous dimethylsulfoxide (1 ml). A sulfur trioxidetrimethylamine complex (70 mg) was added thereto at 0° C., and themixture was stirred at room temperature for 18 hr. Water (1 ml) wasadded dropwise to the reaction solution to stop the reaction. Themixture was extracted with ethyl acetate, and the ethyl acetate layerwas then washed with water and saturated brine and was dried overanhydrous sodium sulfate. The solvent was removed therefrom bydistillation under the reduced pressure, and the residue was purified bychromatography on silica gel using ethyl acetate-hexane for developmentto give the title compound (25 mg, yield 14%).

¹H-NMR (CDCl₃, 400 MHz): δ 1.04 (t, J=7.2 Hz, 3H), 2.85 (q, J=7.2 Hz,2H), 3.80 (s, 3H), 4.02 (s, 3H), 4.04 (s, 3H), 6.46 (d, J=4.6 Hz, 1H),6.57 (d, J=2.4 Hz, 1H), 6.87 (dd, J=2.4 Hz, 8.8 Hz, 1H), 7.44 (s, 1H),7.51 (s, 1H), 7.95 (d, J=8.8 Hz, 1H), 8.50 (d, J=5.1 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 368 (M+1)⁺

Compound 451-{4-(Benzyloxy)-2-[(6,7-dimethoxy-4-quinolyl)oxy]-phenyl}-1-propanone

4-Chloro-6,7-dimethoxyquinoline (111 mg),4-benzyloxy-2-hydroxybenzaldehyde (456 mg), and 4-dimethylaminopyridine(244 mg) were suspended in monochlorobenzene (2 ml), and the suspensionwas stirred at 130° C. overnight. The reaction solution was cooled toroom temperature, water was then added to the reaction solution, and themixture was extracted with ethyl acetate. The ethyl acetate layer wasthen washed with water and saturated brine and was dried over anhydroussodium sulfate. The solvent was removed therefrom by distillation underthe reduced pressure, and the residue was purified by chromatography onsilica gel using ethyl acetate-hexane for development to give4-(benzyloxy)-2-[(6,7-dimethoxy-4-quinolyl)oxy]benzaldehyde.

4-(Benzyloxy)-2-[(6,7-dimethoxy-4-quinolyl)oxy]benzaldehyde wasdissolved in anhydrous tetrahydrofuran (1 ml). A 1 M tetrahydrofuransolution (0.5 ml) of ethylmagnesium bromide was added thereto at 0° C.,and the mixture was stirred at 0° C. for one hr. Water (1 ml) was addeddropwise to the reaction solution to stop the reaction. The mixture wasextracted with ethyl acetate, and the ethyl acetate layer was thenwashed with water and saturated brine and was dried over anhydroussodium sulfate. The solvent was removed by distillation under thereduced pressure to give1-{4-(benzyloxy)-2-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}-1-propanol.

1-{4-(Benzyloxy)-2-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}-1-propanol wasdissolved in anhydrous dimethylsulfoxide (1 ml) to prepare a solution. Asulfur trioxide trimethylamine complex (70 mg) was added to the solutionat 0° C., and the mixture was stirred at room temperature for 18 hr.Water (1 ml) was added dropwise to the reaction solution to stop thereaction. The reaction solution was extracted with ethyl acetate, andthe ethyl acetate layer was then washed with water and saturated brineand was dried over anhydrous sodium sulfate. The solvent was removedtherefrom by distillation under the reduced pressure, and the residuewas purified by chromatography on silica gel using ethyl acetate-hexanefor development to give the title compound (15 mg, yield 7%).

¹H-NMR (CDCl₃, 400 MHz): δ 0.99 (t, J=7.2 Hz, 3H), 2.81 (q, J=7.2 Hz,2H), 3.96 (s, 3H), 3.99 (s, 3H), 5.00 (s, 2H), 6.37 (d, J=5.4 Hz, 1H),6.57 (d, J=2.7 Hz, 1H), 6.88 (dd, J=2.4 Hz, 9.0 Hz, 1H), 7.19 (s, 1H),7.24-7.30 (m, 3H), 7.35 (d, J=5.4 Hz, 1H), 7.38 (s, 1H), 7.43 (s, 1H),7.89 (d, J=8.8 Hz, 1H), 8.42 (d, J=5.1 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 444 (M+1)⁺

Compound 461-{5-Chloro-2-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}-1-propanone

4-Chloro-6,7-dimethoxyquinoline (111 mg), 5-chloro-salicylaldehyde (360mg), and 4-dimethylaminopyridine (244 mg) were suspended inmonochlorobenzene (2 ml), and the suspension was stirred at 130° C. forovernight. The reaction solution was cooled to room temperature, waterwas then added to the reaction solution, and the mixture was extractedwith ethyl acetate. The ethyl acetate layer was then washed with waterand saturated brine and was dried over anhydrous sodium sulfate. Thesolvent was removed therefrom by distillation under the reducedpressure, and the residue was purified by chromatography on silica gelusing ethyl acetate-hexane for development to give5-chloro-2-[(6,7-dimethoxy-4-quinolyl)oxy]benzaldehyde.

5-Chloro-2-[(6,7-dimethoxy-4-quinolyl)oxy]benzaldehyde was dissolved inanhydrous tetrahydrofuran (1 ml) to prepare a solution. A 1 Mtetrahydrofuran solution (0.5 ml) of ethylmagnesium bromide was added tothe solution at 0° C., and the mixture was stirred at 0° C. for one hr.Water (1 ml) was added dropwise to the reaction solution to stop thereaction. The mixture was extracted with ethyl acetate, and the ethylacetate layer was then washed with water and saturated brine and wasdried over anhydrous sodium sulfate. The solvent was removed bydistillation under the reduced pressure to give1-{5-chloro-2-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}-1-propanol.

1-{5-Chloro-2-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}-1-propanol wasdissolved in anhydrous dimethylsulfoxide (1 ml), a sulfur trioxidetrimethylamine complex (70 mg) was added to the solution at 0° C., andthe mixture was stirred at room temperature for 18 hr. Water (1 ml) wasadded dropwise to the reaction solution to stop the reaction. Themixture was extracted with ethyl acetate, and the ethyl acetate layerwas then washed with water and saturated brine and was dried overanhydrous sodium sulfate. The solvent was removed therefrom bydistillation under the reduced pressure, and the residue was purified bychromatography on silica gel using ethyl acetate-hexane for developmentto give the title compound (11 mg, yield 6%).

¹H-NMR (CDCl₃, 400 MHz): δ 1.00 (t, J=7.2 Hz, 3H), 2.83 (q, J=7.2 Hz,2H), 4.00 (s, 6H), 6.40 (d, J=5.4 Hz, 1H), 7.02 (d, J=8.8 Hz, 1H),7.40-7.45 (m, 3H), 7.78 (d, J=2.7 Hz, 1H), 8.46 (d, J=5.2 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 372 (M+1)⁺

Compound 471-{2-[(6,7-Dimethoxy-4-quinolyl)oxy]-5-iodophenyl}-1-propanone

4-Chloro-6,7-dimethoxyquinoline (111 mg), 5-iodosalicylaldehyde (496mg), and 4-dimethylaminopyridine (244 mg) were suspended inmonochlorobenzene (2 ml), and the mixture was stirred at 130° C.overnight. The reaction solution was cooled to room temperature, waterwas then added to the reaction solution, and the mixture was extractedwith ethyl acetate. The ethyl acetate layer was then washed with waterand saturated brine and was dried over anhydrous sodium sulfate. Thesolvent was removed therefrom by distillation under the reducedpressure, and the residue was purified by chromatography on silica gelusing ethyl acetate-hexane for development to give2-[(6,7-dimethoxy-4-quinolyl)oxy]-5-iodobenzaldehyde.

2-[(6,7-Dimethoxy-4-quinolyl)oxy]-5-iodobenzaldehyde was dissolved inanhydrous tetrahydrofuran (1 ml) to prepare a solution. A 1 Mtetrahydrofuran solution (0.5 ml) of ethylmagnesium bromide was added tothe solution at 0° C., and the mixture was stirred at 0° C. for one hr.Water (1 ml) was added dropwise to the reaction solution to stop thereaction. The mixture was extracted with ethyl acetate, and the ethylacetate layer was then washed with water and saturated brine and wasdried over anhydrous sodium sulfate. The solvent was removed bydistillation under the reduced pressure to give1-{2-[(6,7-dimethoxy-4-quinolyl)oxy]-5-iodophenyl}-1-propanol.

1-{2-[(6,7-Dimethoxy-4-quinolyl)oxy]-5-iodophenyl}-1-propanol wasdissolved in anhydrous dimethylsulfoxide (1 ml) to prepare a solution. Asulfur trioxide trimethylamine complex (70 mg) was added to the solutionat 0° C., and the mixture was stirred at room temperature for 18 hr.Water (1 ml) was added dropwise to the reaction solution to stop thereaction. The mixture was extracted with ethyl acetate, and the ethylacetate layer was then washed with water and saturated brine and wasdried over anhydrous sodium sulfate. The solvent was removed therefromby distillation under the reduced pressure, and the residue was purifiedby chromatography on silica gel using ethyl acetate-hexane fordevelopment to give the title compound (9 mg, yield 4%).

¹H-NMR (CDCl₃, 400 MHz): δ 1.06 (t, J=7.2 Hz, 3H), 2.89 (q, J=7.2 Hz,2H), 4.03 (s, 3H), 4.04 (s, 3H), 6.45 (d, J=5.4 Hz, 1H), 7.08 (d, J=8.8Hz, 1H), 7.45 (s, 1H), 7.48 (s, 1H), 7.50 (dd, J=2.7 Hz, 8.3 Hz, 1H),7.84 (d, J=2.7 Hz, 1H), 8.52 (d, J=5.1 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 464 (M+1)⁺

Compound 481-{2-[(6,7-Dimethoxy-4-quinolyl)oxy]-5-methylphenyl}-1-propanone

Under an argon atmosphere,1-{2-[(6,7-dimethoxy-4-quinolyl)oxy]-5-methylphenyl}-1-propanol(compound 9) (31.3 mg) was dissolved in methylene chloride (2 ml), and1,8-diazabicyclo[5.4.0]-7-undecene (30.7 mg) was then added to thesolution, followed by cooling to −78° C.N-Tert-butylbenzenesulfineimidoyl chloride (30.4 mg) was dissolved inmethylene chloride to prepare a solution, the solution was addedthereto, and the mixture was stirred at −78° C. for 50 min. Water wasadded to the reaction solution, and the mixture was extracted withchloroform. The chloroform layer was then washed with saturated brineand was dried over anhydrous magnesium sulfate. The solvent was removedtherefrom by distillation under the reduced pressure, and the residuewas purified by thin layer chromatography using acetone-hexane to givethe title compound (26.2 mg, yield 84%).

¹H-NMR (CDCl₃, 400 MHz): δ 1.05 (t, J=7.3 Hz, 3H), 2.43 (s, 3H), 2.88(q, J=7.3 Hz, 2H), 4.05 (s, 3H), 4.06 (s, 3H), 6.42 (d, J=5.1 Hz, 1H),7.04 (d, J=8.3 Hz, 1H), 7.36 (dd, J=2.2 Hz, 8.3 Hz, 1H), 7.45 (s, 1H),7.55 (s, 1H), 7.67 (d, J=2.0 Hz, 1H), 8.49 (d, J=5.4 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 352 (M+1)⁺

Compound 491-{5-(Tert-butyl)-2-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}-1-propanone

4-Chloro-6,7-dimethoxyquinoline (111 mg),5-tert-butyl-2-hydroxybenzaldehyde (356 mg), and 4-dimethylaminopyridine(244 mg) were suspended in monochlorobenzene (2 ml), and the suspensionwas stirred at 130° C. overnight. The reaction solution was cooled toroom temperature, water was then added to the reaction solution, and themixture was extracted with ethyl acetate. The ethyl acetate layer wasthen washed with water and saturated brine and was dried over anhydroussodium sulfate. The solvent was removed therefrom by distillation underthe reduced pressure, and the residue was purified by chromatography onsilica gel using ethyl acetate-hexane for development to give5-(tert-butyl)-2-[(6,7-dimethoxy-4-quinolyl)oxy]benzaldehyde.

5-(Tert-butyl)-2-[(6,7-dimethoxy-4-quinolyl)oxy]benzaldehyde wasdissolved in anhydrous tetrahydrofuran (1 ml) to prepare a solution. A 1M tetrahydrofuran solution (0.5 ml) of ethylmagnesium bromide was addedto the solution at 0° C., and the mixture was stirred at 0° C. for onehr. Water (1 ml) was added dropwise to the reaction solution to stop thesolution. The mixture was extracted with ethyl acetate, and the ethylacetate layer was then washed with water and saturated brine and wasdried over anhydrous sodium sulfate. The solvent was removed bydistillation under the reduced pressure to give1-{5-(tert-butyl)-2-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}-1-propanol.

1-{5-(Tert-butyl)-2-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}-1-propanolwas dissolved in anhydrous dimethylsulfoxide (1 ml) to prepare asolution. A sulfur trioxide trimethylamine complex (70 mg) was added tothe solution at 0° C., and the mixture was stirred at room temperaturefor 18 hr. Water (1 ml) was added dropwise to the reaction solution tostop the reaction. The mixture was extracted with ethyl acetate, and theethyl acetate layer was then washed with water and saturated brine andwas dried over anhydrous sodium sulfate. The solvent was removedtherefrom by distillation under the reduced pressure. The residue waspurified by chromatography on silica gel using ethyl acetate-hexane fordevelopment to give the title compound (37 mg, yield 19%).

¹H-NMR (CDCl₃, 400 MHz): δ 1.23 (t, J=7.2 Hz, 3H), 1.36 (s, 9H), 2.88(q, J=7.2 Hz, 2H), 4.02 (s, 3H), 4.04 (s, 3H), 6.45 (d, J=5.4 Hz, 1H),7.04 (d, J=8.5 Hz, 1H), 7.44 (s, 1H), 7.52 (s, 1H), 7.56 (dd, J=2.7 Hz,8.6 Hz, 1H), 7.86 (d, J=2.4 Hz, 1H), 8.49 (d, J=5.1 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 394 (M+1)⁺

Compound 501-{2-[(6,7-Dimethoxy-4-quinolyl)oxy]-5-methoxyphenyl}-1-propanone

Under an argon atmosphere,1-{2-[(6,7-dimethoxy-4-quinolyl)oxy]-5-methoxyphenyl}-1-propanol(compound 11) (65.9 mg) was dissolved in methylene chloride (2 ml) toprepare a solution. 1,8-Diazabicyclo[5.4.0]-7-undecene (72 mg) was thenadded to the solution, and the mixture was cooled to −78° C.N-Tert-butylbenzenesulfineimidoyl chloride (71.4 mg) was dissolved inmethylene chloride to prepare a solution, and the solution was added tothe reaction solution. The mixture was stirred at −78° C. for 30 min andat 0° C. for 30 min. Water was added to the reaction solution, and themixture was extracted with chloroform. The chloroform layer was thenwashed with saturated brine and was dried over anhydrous magnesiumsulfate. The solvent was removed therefrom by distillation under thereduced pressure, and the residue was purified by thin layerchromatography using acetone-hexane to give the title compound (56.2 mg,yield 86%).

¹H-NMR (CDCl₃, 400 MHz): δ 1.05 (t, J=7.3 Hz, 3H), 2.88 (q, J=7.3 Hz,2H), 3.89 (s, 3H), 4.06 (s, 6H), 6.39 (d, J=5.1 Hz, 1H), 7.07-7.15 (m,2H), 7.39 (d, J=2.2 Hz, 1H), 7.45 (s, 1H), 7.57 (s, 1H), 8.49 (d, J=5.1Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 368 (M+1)⁺

Compound 511-[2-(6,7-Dimethoxy-4-quinolyl)oxy]-5-(trifluoromethoxy)phenyl]-1-propanone

4-Chloro-6,7-dimethoxyquinoline (111 mg),5-trifluoromethoxysalicylaldehyde (412 mg), and 4-dimethylaminopyridine(244 mg) were suspended in monochlorobenzene (2 ml), and the suspensionwas stirred at 130° C. overnight. The reaction solution was cooled toroom temperature, water was then added to the reaction solution, and themixture was extracted with ethyl acetate. The ethyl acetate layer wasthen washed with water and saturated brine and was dried over anhydroussodium sulfate. The solvent was removed therefrom by distillation underthe reduced pressure, and the residue was purified by chromatography onsilica gel using ethyl acetate-hexane for development to give2-[(6,7-dimethoxy-4-quinolyl)oxy]-5-trifluoromethoxybenzaldehyde.

2-[(6,7-Dimethoxy-4-quinolyl)oxy]-5-trifluoromethoxybenz-aldehyde wasdissolved in anhydrous tetrahydrofuran (1 ml) to prepare a solution. A 1M tetrahydrofuran solution (0.5 ml) of ethylmagnesium bromide was addedto the solution at 0° C., and the mixture was stirred at 0° C. for onehr. Water (1 ml) was added dropwise to the reaction solution to stop thereaction. The mixture was extracted with ethyl acetate, and the ethylacetate layer was then washed with water and saturated brine and wasdried over anhydrous sodium sulfate. The solvent was removed bydistillation under the reduced pressure to give1-{2-[(6,7-dimethoxy-4-quinolyl)oxy]-5-(trifluoromethoxy)phenyl}-1-propanol.

1-{2-[(6,7-Dimethoxy-4-quinolyl)oxy]-5-(trifluoromethoxy)phenyl}-1-propanolwas dissolved in anhydrous dimethylsulfoxide (1 ml) to prepare asolution, a sulfur trioxide trimethylamine complex (70 mg) was added tothe solution at 0° C., and the mixture was stirred at room temperaturefor 18 hr. Water (1 ml) was added dropwise to the reaction solution tostop the reaction. The mixture was extracted with ethyl acetate, and theethyl acetate layer was then washed with water and saturated brine andwas dried over anhydrous sodium sulfate. The solvent was removedtherefrom by distillation under the reduced pressure, and the residuewas purified by chromatography on silica gel using ethyl acetate-hexanefor development to give the title compound (18 mg, yield 8%).

¹H-NMR (CDCl₃, 400 MHz): δ 1.06 (t, J=7.2 Hz, 3H), 2.91 (q, J=7.2 Hz,2H), 4.02 (s, 3H), 4.04 (s, 3H), 6.47 (d, J=5.1 Hz, 1H), 7.15 (d, J=9.0Hz, 1H), 7.38 (dd, J=3.0 Hz, 9.0 Hz, 1H), 7.45 (s, 1H), 7.46 (s, 1H),7.73 (d, J=2.9 Hz, 1H), 8.52 (d, J=5.1 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 422 (M+1)⁺

Compound 521-{2-[(6,7-Dimethoxy-4-quinolyl)oxy]-5-methylphenyl}-1-pentanone

Under an argon atmosphere,1-{2-[(6,7-dimethoxy-4-quinolyl)oxy]-5-methylphenyl}-1-pentanol(compound 10) (45.7 mg) was dissolved in methylene chloride (2 ml) toprepare a solution. 1,8-Diazabicyclo[5.4.0]-7-undecene (37 mg) was thenadded to the solution, and the mixture was cooled to 0° C.N-Tert-butylbenzenesulfineimidoyl chloride (43 mg) was dissolved inmethylene chloride to prepare a solution, the solution was addedthereto, and the mixture was stirred at 0° C. for 40 min. Water wasadded to the reaction solution, and the mixture was extracted withchloroform. The chloroform layer was then washed with saturated brineand was dried over anhydrous sodium sulfate. The solvent was removedtherefrom by distillation under the reduced pressure, and the residuewas purified by thin layer chromatography using acetone-hexane to givethe title compound (27.6 mg, yield 61%).

¹H-NMR (CDCl₃, 400 MHz): δ 0.75 (t, J=7.3 Hz, 3H), 1.17 (m, 2H), 1.55(m, 2H), 2.43 (s, 3H), 2.84 (t, J=7.5 Hz, 2H), 4.05 (s, 3H), 4.06 (s,3H), 6.41 (d, J=5.1 Hz, 1H), 7.05 (d, J=8.3 Hz, 1H), 7.36 (d, J=8.3 Hz,1H), 7.44 (s, 1H), 7.55 (s, 1H), 7.63 (s, 1H), 8.49 (d, J=5.4 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 380 (M+1)⁺

Compound 531-{2-[(6,7-Dimethoxy-4-quinolyl)oxy]-5-methylphenyl}-2-methyl-1-propanone

Under an argon atmosphere,2-[(6,7-dimethoxy-4-quinolyl)oxy]-5-methylbenzaldehyde (105.3 mg) wasdissolved in tetrahydrofuran (3 ml) to prepare a solution, and thesolution was then cooled to −78° C. A 0.68 M tetrahydrofuran solution(0.6 ml) of isopropylmagnesium bromide was added dropwise thereto, andthe mixture was stirred at −78° C. for one hr. A saturated aqueousammonium chloride solution was added to the reaction solution, and themixture was extracted with ethyl acetate. The ethyl acetate layer wasthen washed with saturated brine and was dried over anhydrous sodiumsulfate. The solvent was removed therefrom by distillation under thereduced pressure, and the residue was purified by thin layerchromatography using acetone-hexane to give1-{2-[(6,7-dimethoxy-4-quinolyl)oxy]-5-methylphenyl}-2-methyl-1-propanol(11.5 mg, yield 10%).

1-{2-[(6,7-Dimethoxy-4-quinolyl)oxy]-5-methylphenyl}-2-methyl-1-propanol(9 mg) thus obtained was then dissolved in 2 ml of methylene chlorideunder an argon atmosphere to prepare a solution.1,8-Diazabicyclo[5.4.0]-7-undecene (54 mg) was then added to thesolution, and the mixture was cooled to −78° C.N-Tert-butylbenzenesulfineimidoyl chloride (56 mg) was dissolved inmethylene chloride, and the solution was added thereto. The mixture wasstirred at −78° C. for 3 hr, at 0° C. for one hr, and at roomtemperature overnight. Water was added to the reaction solution, and themixture was extracted with chloroform. The chloroform layer was thenwashed with saturated brine and was dried over anhydrous magnesiumsulfate. The solvent was removed therefrom by distillation under thereduced pressure. The residue was purified by thin layer chromatographyusing acetone-hexane to give the title compound (7.2 mg, yield 80%).

¹H-NMR (CDCl₃, 400 MHz): δ 1.07 (d, J=6.8 Hz, 6H), 2.43 (s, 3H), 3.29(m, 1H), 4.03 (s, 3H), 4.06 (s, 3H), 6.46 (d, J=5.4 Hz, 1H), 7.04 (d,J=8.3 Hz, 1H), 7.34 (dd, J=2.2 Hz, 8.3 Hz, 1H), 7.44 (s, 1H), 7.51 (m,2H), 8.50 (d, J=5.2 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 366 (M+1)⁺

Compound 541-{2-[(6,7-Dimethoxy-4-quinolyl)oxy]-5-methylphenyl}-2,2-dimethyl-1-propanone

4-(2-Bromo-4-methylphenoxy)-6,7-dimethoxyquinoline (compound 4) (100 mg)was dissolved in tetrahydrofuran (6 ml) to prepare a solution which wasthen cooled to −78° C. A 1.59 M n-butyllithium/hexane solution (0.4 ml)was added thereto, and the mixture was stirred at −78° C. for 20 min.Pivaloyl chloride (0.2 ml) was added to the reaction solution, and themixture was stirred at room temperature overnight. Further, water wasadded to the reaction solution, and the mixture was extracted with ethylacetate. The ethyl acetate layer was then washed with water andsaturated brine and was dried over anhydrous sodium sulfate. The solventwas removed therefrom by distillation under the reduced pressure, andthe residue was purified by thin layer chromatography usingacetone-chloroform to give the title compound (21 mg, yield 21%).

¹H-NMR (CDCl₃, 400 MHz): δ 1.23 (s, 9H), 2.41 (s, 3H), 4.00 (s, 3H),4.04 (s, 3H), 6.57 (d, J=5.1 Hz, 1H), 7.02 (d, J=8.3 Hz, 1H), 7.07 (m,1H), 7.22 (dd, J=1.5 Hz, 8.3 Hz, 1H), 7.43 (s, 1H), 7.44 (s, 1H), 8.51(d, J=5.1 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 380 (M+1)⁺

Compound 551-{2-[(6,7-Dimethoxy-4-quinolyl)oxy]-5-methylphenyl}-3,3-dimethyl-1-butanone

4-(2-Bromo-4-methylphenoxy)-6,7-dimethoxyquinoline (100 mg) wasdissolved in tetrahydrofuran (6 ml) to prepare a solution which was thencooled to −78° C. A 1.59 M n-butyllithium/hexane solution (0.4 ml) wasadded thereto, and the mixture was stirred at −78° C. for 20 min.Tert-butylacetyl chloride (0.2 ml) was added to the reaction solution,and the mixture was stirred at room temperature overnight. Further,water was added to the reaction solution, and the mixture was extractedwith ethyl acetate. The ethyl acetate layer was then washed with waterand saturated brine and was dried over anhydrous sodium sulfate. Thesolvent was removed therefrom by distillation under the reducedpressure, and the residue was purified by thin layer chromatographyusing acetone-chloroform to give the title compound (15 mg, yield 14%).

¹H-NMR (CDCl₃, 400 MHz): δ 0.92 (s, 9H), 2.43 (s, 3H), 2.77 (s, 2H),4.04 (s, 3H), 4.06 (s, 3H), 6.41 (d, J=5.4 Hz, 1H), 7.05 (d, J=8.3 Hz,1H), 7.35 (dd, J=2.2 Hz, 8.8 Hz, 1H), 7.50 (s, 1H), 7.52 (d, J=2.2 M/Z):5 Hz, 1H), 7.55 (s, 1H), 8.49 (d, J=4.9 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 394 (M+1)⁺

Compound 563-Cyclopentyl-1-{2-[(6,7-dimethoxy-4-quinolyl)oxy]-5-methylphenyl}-1-propanone

4-(2-Bromo-4-methylphenoxy)-6,7-dimethoxyquinoline (100 mg) wasdissolved in tetrahydrofuran (6 ml) to prepare a solution which was thencooled to −78° C. A 1.59 M n-butyllithium/hexane solution (0.4 ml) wasadded to the cooled solution, and the mixture was stirred at −78° C. for20 min. 3-Cyclopentylpropionyl chloride (0.2 ml) was added to thereaction solution, and the mixture was stirred at room temperatureovernight. Further, water was added to the reaction solution, and themixture was extracted with ethyl acetate. The ethyl acetate layer wasthen washed with water and saturated brine and was dried over anhydroussodium sulfate. The solvent was removed therefrom by distillation underthe reduced pressure, and the residue was purified by thin layerchromatography using acetone-chloroform to give the title compound (9mg, yield 8%).

¹H-NMR (CDCl₃, 400 MHz): δ 0.88-1.84 (m, 11H), 2.44 (s, 3H), 2.84 (m,2H), 4.05 (s, 3H), 4.07 (s, 3H), 6.41 (d, J=5.4 Hz, 1H), 7.05 (d, J=8.3Hz, 1H), 7.38 (dd, J=2.2 Hz, 8.3 Hz, 1H), 7.55 (s, 1H), 7.56 (s, 1H),7.64 (d, J=1.7 Hz, 1H), 8.50 (d, J=5.4 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 420 (M+1)⁺

Compound 571-{2-[(6,7-Dimethoxy-4-quinolyl)oxy]phenyl}-3-phenyl-2-propen-1-one

4-Chloro-6,7-dimethoxyquinoline (100 mg), 2-hydroxychalcone (300 mg),and 4-dimethylaminopyridine (164 mg) were suspended in o-dichlorobenzene(6 ml), and the suspension was stirred at 130° C. overnight. Thereaction solution was cooled to room temperature, water was then addedto the reaction solution, and the mixture was extracted with ethylacetate. The ethyl acetate layer was then washed with water andsaturated brine and was dried over anhydrous sodium sulfate. The solventwas removed therefrom by distillation under the reduced pressure, andthe residue was purified by column chromatography using acetone-hexaneto give the title compound (30 mg, yield 16%).

¹H-NMR (CDCl₃, 400 MHz): δ 3.74 (s, 3H), 3.88 (s, 1H), 3.97 (s, 3H),4.01 (s, 1H), 6.41 (d, J=5.4 Hz, 1H), 7.12-7.50 (m, 9H), 7.59 (t, J=8.0Hz, 1H), 7.80 (d, J=8.0 Hz, 1H), 8.45 (d, J=5.4 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 412 (M+1)⁺

Compound 58(Cyclopentyl){2-[(6,7-dimethoxy-4-quinolyl)oxy]-5-methylphenyl}methanone

4-(2-Bromo-4-methylphenoxy)-6,7-dimethoxyquinoline (100 mg) wasdissolved in tetrahydrofuran (6 ml) to prepare a solution which was thencooled to −78° C. A 1.59 M n-butyllithium/hexane solution (0.35 ml) wasadded to the cooled solution, and the mixture was stirred at −78° C. for20 min. Cyclopentanecarbonyl chloride (0.2 ml) was added to the reactionsolution, and the mixture was stirred at room temperature for 7 hr.Further, water was added to the reaction solution, and the mixture wasextracted with ethyl acetate. The ethyl acetate layer was then washedwith water and saturated brine and was dried over anhydrous sodiumsulfate. The solvent was removed therefrom by distillation under thereduced pressure, and the residue was purified by thin layerchromatography using acetone-chloroform to give the title compound (14mg, yield 13%).

¹H-NMR (CDCl₃, 400 MHz): δ 1.41-1.83 (m, 8H), 2.43 (s, 3H), 3.52 (tt,J=7.1, 8.3 Hz, 1H), 4.03 (s, 3H), 4.06 (s, 3H), 6.45 (d, J=5.2 Hz, 1H),7.04 (d, J=8.1 Hz, 1H), 7.34 (dd, J=1.7 Hz, 8.3 Hz, 1H), 7.46 (s, 1H),7.53 (s, 1H), 7.55 (d, J=2.2 Hz, 1H), 8.49 (d, J=5.4 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 392 (M+1)⁺

Compound 59(Cyclohexyl){2-[(6,7-dimethoxy-4-quinolyl)oxy]-5-methylphenyl}methanone

4-(2-Bromo-4-methylphenoxy)-6,7-dimethoxyquinoline (101 mg) wasdissolved in tetrahydrofuran (5 ml) to prepare a solution which was thencooled to −78° C. A 1.59 M n-butyllithium/hexane solution (0.4 ml) wasadded to the cooled solution, and the mixture was stirred at −78° C. for20 min. Cyclohexanecarbonyl chloride (0.2 ml) was added to the reactionsolution, and the mixture was stirred at room temperature for 3 hr.Further, water was added to the reaction solution, and the mixture wasextracted with ethyl acetate. The ethyl acetate layer was then washedwith water and saturated brine and was dried over anhydrous sodiumsulfate. The solvent was removed therefrom by distillation under thereduced pressure, and the residue was purified by thin layerchromatography using acetone-chloroform to give the title compound (17mg, yield 16%).

¹H-NMR (CDCl₃, 400 MHz): δ 0.88-1.70 (m, 10H), 2.35 (s, 3H), 2.94 (m,1H), 3.97 (s, 3H), 3.99 (s, 3H), 6.35 (d, J=5.4 Hz, 1H), 6.97 (d, J=8.3Hz, 1H), 7.27 (dd, J=2.2 Hz, 8.3 Hz, 1H), 7.39 (s, 1H), 7.42 (d, J=1.9Hz, 1H), 7.47 (s, 1H), 8.42 (d, J=5.1 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 406 (M+1)⁺

Compound 60{2-[(6,7-Dimethoxy-4-quinolyl)oxy]-5-methylphenyl}(2-furyl)methanone

4-(2-Bromo-4-methylphenoxy)-6,7-dimethoxyquinoline (100 mg) wasdissolved in tetrahydrofuran (6 ml) to prepare a solution which was thencooled to −78° C. A 1.59 M n-butyllithium/hexane solution (0.35 ml) wasadded to the cooled solution, and the mixture was stirred at −78° C. for20 min. 2-Furancarbonyl chloride (0.2 ml) was added to the reactionsolution, and the mixture was stirred at room temperature for 7 hr.Further, water was added to the reaction solution, and the mixture wasextracted with ethyl acetate. The ethyl acetate layer was then washedwith water and saturated brine and was dried over anhydrous sodiumsulfate. The solvent was removed therefrom by distillation under thereduced pressure, and the residue was purified by thin layerchromatography using acetone-chloroform to give the title compound (34mg, yield 33%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.49 (s, 3H), 3.99 (s, 3H), 4.09 (s, 3H),6.49-6.51 (m, 2H), 6.64 (d, J=6.1 Hz, 1H), 7.18 (d, J=8.3 Hz, 1H), 7.37(s, 1H), 7.46 (dd, J=2.2 Hz, 8.3 Hz, 1H), 7.53 (m, 1H), 7.57 (m, 1H),7.86 (s, 1H), 8.72 (d, J=5.9 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 390 (M+1)⁺

Compound 61{2-[(6,7-Dimethoxy-4-quinolyl)oxy]-5-methylphenyl}(5-isoxazolyl)methanone

4-(2-Bromo-4-methylphenoxy)-6,7-dimethoxyquinoline (100 mg) wasdissolved in tetrahydrofuran (6 ml) to prepare a solution which was thencooled to −78° C. A 1.59 M n-butyllithium/hexane solution (0.4 ml) wasadded to the solution, and the mixture was stirred at −78° C. for 20min. Isoxazole-5-carbonyl chloride (0.2 ml) was added to the reactionsolution, and the mixture was stirred at room temperature overnight.Further, water was added to the reaction solution, and the mixture wasextracted with ethyl acetate. The ethyl acetate layer was then washedwith water and saturated brine and was dried over anhydrous sodiumsulfate. The solvent was removed therefrom by distillation under thereduced pressure, and the residue was purified by thin layerchromatography using acetone-chloroform to give the title compound (27mg, yield 26%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.48 (s, 3H), 4.01 (s, 3H), 4.02 (s, 3H),6.46 (d, J=5.4 Hz, 1H), 6.81 (d, J=1.9 Hz, 1H), 7.13 (d, J=8.3 Hz, 1H),7.24 (s, 1H), 7.40 (s, 1H), 7.49 (dd, J=1.9, 8.3 Hz, 1H), 7.59 (d, J=1.7Hz, 1H), 8.25 (d, J=1.9 Hz, 1H), 8.46 (d, J=5.4 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 391 (M+1)⁺

Compound 62 {2-[(6,7-Dimethoxy-4-quinolyl)oxy]-phenyl}(phenyl)-methanone

4-Chloro-6,7-dimethoxyquinoline (58 mg), 2-hydroxybenzophenone (271 mg),and 4-dimethylaminopyridine (166 mg) were suspended in o-dichlorobenzene(5 ml), and the suspension was stirred at 160° C. for 4 hr. The reactionsolution was cooled to room temperature, and the solvent was thenremoved therefrom by distillation under the reduced pressure. Chloroformwas added to the residue, and the mixture was washed with a 1 N aqueouspotassium hydroxide solution and saturated brine and was dried overanhydrous sodium sulfate. The solvent was removed therefrom bydistillation under the reduced pressure, and the residue was purified bycolumn chromatography using chloroform and by thin layer chromatographyusing acetone-hexane to quantitatively give 110.4 mg of the titlecompound.

¹H-NMR (CDCl₃, 400 MHz): δ 3.82 (s, 3H), 3.99 (s, 3H), 6.43 (d, J=5.1Hz, 1H), 6.93 (s, 1H), 7.26 (d, J=8.3 Hz, 1H), 7.28-7.34 (m, 3H),7.39-7.48 (m, 2H), 7.59-7.72 (m, 4H), 8.44 (d, J=5.4 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 386 (M+1)⁺

Compound 63 {2-[(6,7-Dimethoxy-4-quinolyl)oxy]-phenyl}(phenyl)-methanonehydrochloride

4-Chloro-6,7-dimethoxyquinoline (0.92 g) and 2-hydroxybenzophenone (1.64g) were stirred at 180° C. for one hr, and the reaction solution wascooled to room temperature. Chloroform was then added to the reactionsolution, and separation was carried out with a 10% aqueous sodiumhydroxide solution. The organic layer was washed with a saturatedaqueous sodium hydrogencarbonate solution and saturated brine and wasdried over anhydrous magnesium sulfate. The solvent was removedtherefrom by distillation under the reduced pressure, and the residuewas purified by column chromatography on silica gel usinghexane-acetone. Thereafter, 10% hydrochloric acid-methanol (10 ml) wasadded to the product, followed by concentration. The concentrate wassuspended in ether. The suspension was filtered to give the titlecompound (174 mg, yield 10%).

¹H-NMR (CDCl₃, 400 MHz): δ 3.92 (s, 3H), 4.13 (s, 3H), 6.66 (d, J=6.4Hz, 1H), 7.15 (s, 1H), 7.35-7.41 (m, 3H), 7.52-7.61 (m, 2H), 7.67-7.79(m, 4H), 8.08 (s, 1H), 8.44 (dd, J=6.6 Hz, 6.6 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 386 (M-HCl+1)⁺

Compound 64{2-[(6,7-Dimethoxy-4-quinolyl)oxy]-4-methoxyphenyl}-(phenyl)methanone

4-Chloro-6,7-dimethoxyquinoline (56.5 mg),2-hydroxy-4-methoxybenzophenone (286 mg), and 4-dimethylaminopyridine(163 mg) were suspended in o-dichlorobenzene (5 ml), and the suspensionwas stirred at 160° C. for 4 hr. The reaction solution was cooled toroom temperature, and the solvent was then removed therefrom bydistillation under the reduced pressure. Chloroform was added to theresidue, and the mixture was washed with a 1 N aqueous potassiumhydroxide solution and saturated brine and was dried over anhydroussodium sulfate. The solvent was removed therefrom by distillation underthe reduced pressure, and the residue was purified by columnchromatography using chloroform and by thin layer chromatography usingacetone-hexane to give the title compound (14.5 mg, yield 14%).

¹H-NMR (CDCl₃, 400 MHz): δ 3.87 (s, 3H), 3.89 (s, 3H), 3.99 (s, 3H),6.42 (d, J=5.4 Hz, 1H), 6.76 (d, J=2.4 Hz, 1H), 6.92 (s, 1H), 6.96 (dd,J=2.4 Hz, 8.8 Hz, 1H), 7.24-7.33 (m, 3H), 7.41 (m, 1H), 7.61-7.66 (m,2H), 7.69 (d, J=8.8 Hz, 1H), 8.43 (d, J=5.1 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 416 (M+1)⁺

Compound 65{2-[(6,7-Dimethoxy-4-quinolyl)oxy]-4-methoxyphenyl}(4-methylphenyl)methanone

4-Chloro-6,7-dimethoxyquinoline (56 mg),2-hydroxy-4-methoxy-4′-methylbenzophenone (242 mg), and4-dimethylaminopyridine (122 mg) were suspended in o-dichlorobenzene (1ml), and the suspension was stirred at 140° C. for 4 hr. The reactionsolution was cooled to room temperature, and the solvent was removed bydistillation under the reduced pressure. Water was then added to theresidue, and the mixture was extracted with chloroform. The chloroformlayer was washed with water and was dried over anhydrous sodium sulfate.The solvent was removed therefrom by distillation under the reducedpressure. The residue was purified by thin layer chromatography usingacetone-hexane to give the title compound (46 mg, yield 43%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.31 (s, 3H), 3.88 (s, 3H), 3.89 (s, 3H),4.01 (s, 3H), 6.43 (d, J=5.3 Hz, 1H), 6.77 (d, J=2.4 Hz, 1H), 6.95 (dd,J=8.5 Hz, 2.4 Hz, 1H), 6.98 (s, 1H), 7.07 (d, J=8.0 Hz, 2H), 7.35 (s,1H), 7.54 (d, J=8.0 Hz, 2H), 7.66 (d, J=8.5 Hz, 1H), 8.43 (d, J=5.3 Hz,1H)

Mass spectrometric value (ESI−MS, m/z): 430 (M+1)⁺

Compound 66{2-[(6,7-Dimethoxy-4-quinolyl)oxy]-4-octoxyphenyl}-(phenyl)methanone

4-Chloro-6,7-dimethoxyquinoline (100 mg),2-hydroxy-4-n-octoxybenzophenone (652 mg), and 4-dimethylaminopyridine(244 mg) were suspended in o-dichlorobenzene (1 ml), and the suspensionwas stirred at 120° C. for 6 hr. The reaction solution was cooled toroom temperature, and the solvent was removed by distillation under thereduced pressure. Water was then added to the residue, and the mixturewas extracted with chloroform. The chloroform layer was washed withwater and was dried over anhydrous sodium sulfate. The solvent wasremoved therefrom by distillation under the reduced pressure, and theresidue was purified by column chromatography using acetone-hexane togive the title compound (85 mg, yield 33%).

¹H-NMR (CDCl₃, 400 MHz): δ 0.89 (t, J=6.8 Hz, 3H), 1.23-1.50 (m, 10H),1.82 (m, 2H), 3.87 (s, 3H), 3.99-4.06 (m, 5H), 6.42 (d, J=5.3 Hz, 1H),6.74 (d, J=2.2 Hz, 1H), 6.92 (s, 1H), 6.94 (dd, J=2.2 Hz, 8.6 Hz, 1H),7.27 (m, 2H), 7.30 (s, 1H), 7.39 (m, 1H), 7.63 (m, 2H), 7.67 (d, J=8.6Hz, 1H), 8.43 (d, J=5.3 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 514 (M+1)⁺

Compound 67 4-Benzoyl-3-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl2-methylacrylate

4-Chloro-6,7-dimethoxyquinoline (56 mg),4-methacryloxy-2-hydroxybenzophenone (282 mg), and4-dimethylaminopyridine (122 mg) were suspended in o-dichlorobenzene (1ml), and the suspension was stirred at 140° C. for 4 hr. The reactionsolution was cooled to room temperature, and the solvent was removed bydistillation under the reduced pressure. Water was then added to theresidue, and the mixture was extracted with chloroform. The chloroformlayer was washed with water and was dried over anhydrous sodium sulfate.The solvent was removed therefrom by distillation under the reducedpressure, and the residue was purified by thin layer chromatographyusing acetone-hexane to give the title compound (21 mg, yield 18%).

¹H-NMR (CDCl₃, 400 MHz): δ 1.78 (s, 3H), 4.04 (s, 3H), 4.06 (s, 3H),5.52 (m, 1H), 5.82 (m, 1H), 6.75 (d, J=5.1 Hz, 1H), 7.10 (d, J=2.0 Hz,1H), 7.16 (dd, J=8.6 Hz, 2.2 Hz, 1H), 7.31-8.48 (m, 8H), 8.61 (d, J=5.1Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 470 (M+1)⁺

Compound 68{5-Chloro-2-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}-(phenyl)methanone

4-Chloro-6,7-dimethoxyquinoline (57.5 mg),5-chloro-2-hydroxybenzophenone (309 mg), and 4-dimethylaminopyridine(173 mg) were suspended in o-dichlorobenzene (5 ml), and the suspensionwas stirred at 160° C. for 5 hr. The mixture was cooled to roomtemperature, and the solvent was then removed therefrom by distillationunder the reduced pressure, and chloroform was added to the residue. Themixture was washed with a 1 N aqueous potassium hydroxide solution andsaturated brine and was dried over anhydrous magnesium sulfate. Thesolvent was removed therefrom by distillation under the reducedpressure, and the residue was purified by column chromatography usingchloroform and by thin layer chromatography using acetone-hexane toquantitatively give 114 mg of the title compound.

¹H-NMR (CDCl₃, 400 MHz): δ 3.82 (s, 3H), 3.99 (s, 3H), 6.44 (d, J=5.1Hz, 1H), 6.90 (s, 1H), 7.21 (d, J=8.8 Hz, 1H), 7.31-7.37 (m, 3H),7.46-7.51 (m, 1H), 7.58 (dd, J=2.7 Hz, 8.8 Hz, 1H), 7.63 (d, J=2.7 Hz,1H), 7.68-7.72 (m, 2H), 8.45 (d, J=5.4 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 420 (M+1)⁺

Compound 69{5-Chloro-2-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}-(phenyl)methanonehydrochloride

4-Chloro-6,7-dimethoxyquinoline (1.00 g) and5-chloro-2-hydroxybenzophenone (1.46 g) were stirred at 170° C. for onehr, and the reaction solution was cooled to room temperature. Chloroformwas then added to the reaction solution, and separation was carried outwith a 10% aqueous sodium hydroxide solution. The organic layer waswashed with a saturated aqueous sodium hydrogencarbonate solution andsaturated brine and was dried over anhydrous magnesium sulfate. Thesolvent was removed therefrom by distillation under the reducedpressure, and the residue was purified by column chromatography onsilica gel using hexane-acetone. Thereafter, 10% hydrochloricacid-methanol (10 ml) was added to the product, followed byconcentration. The concentrate was suspended in ether, and thesuspension was filtered to give the title compound (225 mg, yield 11%).

¹H-NMR (CDCl₃, 400 MHz): δ 3.91 (s, 3H), 4.12 (s, 3H), 6.68 (d, J=5.6Hz, 1H), 7.11 (s, 1H), 7.32 (d, J=8.5 Hz, 1H), 7.38-7.43 (m, 2H),7.54-7.60 (m, 1H), 7.66-7.74 (m, 4H), 8.08 (s, 1H), 8.48 (brs, 1H)

Mass spectrometric value (ESI−MS, m/z): 420 (M-HCl+1)⁺

Compound 70{5-Bromo-2-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}-(phenyl)methanone

4-Chloro-6,7-dimethoxyquinoline (56.1 mg), 5-bromo-2-hydroxybenzophenone(361 mg), and 4-dimethylaminopyridine (168 mg) were suspended ino-dichlorobenzene (5 ml), and the suspension was stirred at 160° C. for7 hr. The reaction solution was cooled to room temperature, and thesolvent was then removed therefrom by distillation under the reducedpressure. Chloroform was added to the residue, and mixture was washedwith a 1 N aqueous potassium hydroxide solution and saturated brine andwas dried over anhydrous magnesium sulfate. The solvent was removedtherefrom by distillation under the reduced pressure, and the residuewas purified by column chromatography using chloroform and by thin layerchromatography using acetone-hexane to give the title compound (110 mg,yield 94%).

¹H-NMR (CDCl₃, 400 MHz): δ 3.82 (s, 3H), 3.99 (s, 3H), 6.45 (d, J=5.4Hz, 1H), 6.83 (s, 1H), 7.15 (d, J=8.6 Hz, 1H), 7.31-7.37 (m, 3H),7.46-7.51 (m, 1H), 7.67-7.75 (m, 3H), 7.78 (d, J=2.4 Hz, 1H), 8.45 (d,J=5.4 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 465 (M+1)⁺

Compound 71{2-[(6,7-Dimethoxy-4-quinolyl)oxy]-5-methylphenyl}-(phenyl)methanone

4-Chloro-6,7-dimethoxyquinoline (58.6 mg),2-hydroxy-5-methylbenzophenone (276 mg), and 4-dimethylaminopyridine(156 mg) were suspended in o-dichlorobenzene (5 ml), and the suspensionwas stirred at 160° C. for 5 hr. The reaction solution was cooled toroom temperature, and the solvent was then removed therefrom bydistillation under the reduced pressure. Chloroform was added to theresidue, and the mixture was washed with a 1 N aqueous potassiumhydroxide solution and saturated brine and was dried over anhydroussodium sulfate. The solvent was removed therefrom by distillation underthe reduced pressure, and the residue was purified by columnchromatography using chloroform and by thin layer chromatography usingacetone-hexane to give the title compound (98.9 mg, yield 95%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.46 (s, 3H), 3.81 (s, 3H), 3.98 (s, 3H),6.40 (d, J=5.4 Hz, 1H), 6.89 (s, 1H), 7.16 (d, J=8.3 Hz, 1H), 7.27-7.33(m, 3H), 7.40-7.48 (m, 3H), 7.67-7.71 (m, 2H), 8.42 (d, J=5.1 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 400 (M+1)⁺

Compound 72{2-[(6,7-Dimethoxy-4-quinolyl)oxy]-5-methylphenyl}-(phenyl)methanonehydrochloride

4-Chloro-6,7-dimethoxyquinoline (1.00 g) and2-hydroxy-5-methylbenzophenone (1.14 g) were stirred at 170° C. for onehr. The reaction solution was cooled to room temperature. Chloroform wasthen added to the reaction solution, and separation was carried out witha 10% aqueous sodium hydroxide solution. The organic layer was washedwith a saturated aqueous sodium hydrogencarbonate solution and saturatedbrine and was dried over anhydrous magnesium sulfate. The solvent wasremoved therefrom by distillation under the reduced pressure, and theresidue was purified by column chromatography on silica gel usinghexane-acetone. Thereafter, 10% hydrochloric acid-methanol (10 ml) wasadded to the product, followed by concentration. The concentrate wassuspended in ether, and the suspension was filtered to give the titlecompound (234 mg, yield 12%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.51 (s, 3H), 3.91 (s, 3H), 4.12 (s, 3H),6.66 (d, J=6.4 Hz, 1H), 7.11 (s, 1H), 7.23 (d, J=8.3 Hz, 1H), 7.38 (t,J=7.6 Hz, 1H), 7.50-7.57 (m, 4H), 7.65-7.70 (m, 2H), 8.06 (s, 1H), 8.43(brs, 1H)

Mass spectrometric value (ESI−MS, m/z): 400 (M-HCl+1)⁺

Compound 73[4-(Tert-butyl)phenyl]{2-[(6,7-dimethoxy-4-quinolyl)oxy]-5-methylphenyl}methanone

4-(2-Bromo-4-methylphenoxy)-6,7-dimethoxyquinoline (100 mg) wasdissolved in tetrahydrofuran (6 ml) to prepare a solution which was thencooled to −78° C. A 1.59 M n-butyllithium/hexane solution (0.35 ml) wasadded to the cooled solution, and the mixture was stirred at −78° C. for20 min. 4-Tert-butylphenylcarbonyl chloride (0.15 ml) was added to thereaction solution, and the mixture was stirred at room temperature for30 min. Further, water was added to the reaction solution, and themixture was extracted with ethyl acetate. The ethyl acetate layer wasthen washed with water and saturated brine and was dried over anhydroussodium sulfate. The solvent was removed therefrom by distillation underthe reduced pressure, and the residue was purified by thin layerchromatography using acetone-chloroform to give the title compound (31mg, yield 25%).

¹H-NMR (CDCl₃, 400 MHz): δ 1.23 (s, 9H), 2.46 (s, 3H), 3.84 (s, 3H),3.98 (s, 3H), 6.48 (d, J=5.1 Hz, 1H), 7.07 (s, 1H), 7.16 (d, J=8.3 Hz,1H), 7.28 (d, J=8.8 Hz, 2H), 7.30 (s, 1H), 7.41 (m, 1H), 7.43 (s, 1H),7.64 (d, J=8.6 Hz, 2H), 8.43 (d, J=4.9 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 456 (M+1)⁺

Compound 74{2-[(6,7-Dimethoxy-4-quinolyl)oxy]-5-methoxyphenyl}-(phenyl)methanone

A mixture of 4-chloro-6,7-dimethoxyquinoline (93 mg) with2-hydroxy-5-methoxybenzophenone (462 mg) was stirred at 180° C. for 9hr. The reaction solution was cooled to room temperature and waspurified by column chromatography on silica gel using acetone-hexane togive the title compound (14 mg, yield 8%).

¹H-NMR (CDCl₃, 500 MHz): δ 3.87 (s, 3H), 3.89 (s, 3H), 4.00 (s, 3H),6.42 (d, J=5.5 Hz, 1H), 6.76 (d, J=2.4 Hz, 1H), 6.92 (s, 1H), 6.96 (dd,J=2.4 Hz, 8.6 Hz, 1H), 7.26-7.29 (m, 3H), 7.31 (s, 1H), 7.41 (t, J=7.3Hz, 1H), 7.63 (d, J=6.7 Hz, 1H), 7.69 (d, J=8.6 Hz, 1H), 8.43 (d, J=5.5Hz, 1H)

Mass spectrometric value (FD−MS, m/z): 415 (M⁺)

Compound 75{5-Chloro-2-[(6,7-dimethoxy-4-quinolyl)oxy]-4-methylphenyl}(phenyl)methanone

4-Chloro-6,7-dimethoxyquinoline (100 mg),5-chloro-2-hydroxy-4-methylbenzophenone (443 mg), and4-dimethylaminopyridine (220 mg) were suspended in o-dichlorobenzene (1ml), and the mixture was stirred at 140° C. for 7 hr. The reactionsolution was cooled to room temperature, and the solvent was removed bydistillation under the reduced pressure. Water was then added to theresidue, and the mixture was extracted with chloroform. The chloroformlayer was washed with water and was dried over anhydrous sodium sulfate.The solvent was removed therefrom by distillation under the reducedpressure, and the residue was purified by column chromatography usingacetone-hexane to give the title compound (175 mg, yield 90%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.48 (s, 3H), 3.84 (s, 3H), 4.00 (s, 3H),6.43 (d, J=5.4 Hz, 1H), 6.91 (s, 1H), 7.14 (s, 1H), 7.32 (m, 3H), 7.46(m, 1H), 7.67 (m, 3H), 7.44 (d, J=5.4 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 434 (M+1)⁺

Compound 76{2-[(6,7-Dimethoxy-4-quinolyl)oxy]-4,5-dimethylphenyl}-(phenyl)methanonehydrochloride

Commercially available 3,4-dimethylanisole (409 mg) was dissolved innitromethane (6 ml) to prepare a solution. Lithium perchlorate (1.9 g)and benzoyl chloride (843 mg) were added to the solution, scandiumtrifluoromethanesulfonate (148 mg) was then added thereto, and themixture was stirred at room temperature for 3 days. A saturated aqueoussodium hydrogencarbonate solution was added to the reaction solution,and the mixture was extracted with chloroform. The organic layer waswashed with saturated brine, was dried over sodium sulfate and wasconcentrated. The residue was subjected to separation and purificationby column chromatography on silica gel using hexane/ethyl acetate as asolvent to give (4,5-dimethyl-2-methoxyphenyl)(phenyl)methanone (667 mg,yield 93%).

(4,5-Dimethyl-2-methoxyphenyl)(phenyl)methanone (650 mg) was dissolvedin dimethylformamide (10 ml) to prepare a solution. Sodium thiomethoxide(379 mg) was added to the solution, and the mixture was stirred whileheating under reflux overnight. The reaction solution was cooled to roomtemperature, water was added thereto, and the mixture was extracted withethyl acetate. The organic layer was washed with saturated brine, wasdried over sodium sulfate and was concentrated. The residue wassubjected to separation and purification by column chromatography onsilica gel using hexane/ethyl acetate as a solvent to give(4,5-dimethyl-2-hydroxy-phenyl)(phenyl)methanone. The(4,5-dimethyl-2-hydroxy-phenyl)(phenyl)methanone (40 mg) thus obtainedand 4-chloro-6,7-dimethoxyquinoline (150 mg) were added too-dichlorobenzene (0.2 ml), and the mixture was heated at 180° C. fortwo days. The reaction solution was concentrated and was subjected toseparation and purification by column chromatography on silica gel usinghexane-ethyl acetate. Subsequently, a hydrochloric acid-methanol mixedsolution was added thereto, the solvent was removed by distillation, andthe residue was suspended in ethyl acetate. The solid thus obtained wascollected by filtration, was washed with ethyl acetate, and was thendried to give the title compound (9.2 mg, yield 11%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.40 (s, 3H), 2.43 (s, 3H), 3.93 (s, 3H),4.12 (s, 3H), 6.65 (d, J=6.6 Hz, 1H), 7.11 (s, 1H), 7.13 (s, 1H), 7.36(dd, J=7.6 Hz, 7.6 Hz, 2H), 7.49 (s, 1H), 7.51 (dd, J=7.3 Hz, 7.3 Hz,1H), 7.66 (d, J=7.1 Hz, 2H), 8.06 (s, 1H), 8.42 (dd, J=6.6 Hz, 6.6 Hz,1H)

Mass spectrometric value (ESI−MS, m/z): 414 (M-HCl+1)⁺

Compound 77 {3-[(6,7-Dimethoxy-4-quinolyl)oxy]phenyl}(phenyl)-methanone

4-Chloro-6,7-dimethoxyquinoline (112 mg) and 3-hydroxybenzophenone (297mg) were mixed together, and the mixture was heated at 170° C. for 10min. A saturated aqueous sodium hydrogencarbonate solution was addedthereto, and the mixture was extracted with ethyl acetate. The organiclayer was washed with saturated brine, was dried over sodium sulfate,and was then concentrated. The residue was subjected to separation andpurification by column chromatography on silica gel using hexane-acetoneas a solvent to give the title compound (126 mg, yield 65%).

¹H-NMR (CDCl₃, 400 MHz): δ 4.05 (s, 3H), 4.07 (s, 3H), 6.53 (d, J=5.4Hz, 1H), 7.42-7.65 (m, 8H), 7.72 (dd, J=1.5 Hz, 6.3 Hz, 1H), 7.83 (dd,J=1.2 Hz, 8.3 Hz, 2H), 8.53 (d, J=5.1 Hz, 1H)

Mass spectrometric value (FD−MS, m/z): 385 (M⁺)

Compound 78 Synthesis of{4-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}(3-methylphenyl)methanone

Commercially available anisole (541 mg) and 3-methylbenzoyl chloride(773 mg) were dissolved in nitromethane (5 ml) to prepare a solution.Scandium trifluoromethanesulfonate (49 mg) was added to the solution,and the mixture was stirred at 60° C. overnight. A saturated aqueoussodium hydrogencarbonate solution was added thereto, and the mixture wasextracted with chloroform. The organic layer was washed with saturatedbrine, was dried over sodium sulfate, and was then concentrated. Theresidue was subjected to separation and purification by columnchromatography on silica gel using hexane-acetone as a solvent to give(4-methoxyphenyl)(3-methylphenyl)methanone (633 mg, yield 56%).

(4-Methoxyphenyl)(3-methylphenyl)methanone (603 mg) was dissolved indichloromethane (3 ml) to prepare a solution. A borontribromide-dichloromethane solution (1.0 M) (11 ml) was added to thesolution, and the mixture was stirred at room temperature for 2 days.The reaction solution was poured into ice-cooled water, and the mixturewas extracted with chloroform. The organic layer was washed withsaturated brine, was dried over sodium sulfate, and was thenconcentrated. The residue was subjected to separation and purificationby column chromatography on silica gel using hexane/ethyl acetate as asolvent to give (4-hydroxyphenyl)(3-methylphenyl)methanone (1.50 g,yield 56%).

(4-Hydroxyphenyl)(3-methylphenyl)methanone (307 mg) was dissolved inxylene to prepare a solution. 4-Dimethylaminopyridine (194 mg) and4-chloro-6,7-dimethoxyquinoline (342 mg) were added to the solution, andthe mixture was heated under reflux for 23 hr. A saturated aqueoussodium hydrogencarbonate solution was added thereto, and the mixture wasextracted with chloroform. The organic layer was dried over sodiumsulfate and was then concentrated. The residue was subjected toseparation and purification by column chromatography on silica gel usinghexane-ethyl acetate, chloroform, and hexane-acetone as solvents to givethe title compound (262 mg, yield 45%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.44 (s, 3H), 4.03 (s, 3H), 4.06 (s, 3H),6.66 (d, J=4.9 Hz, 1H), 7.27 (d, J=8.6 Hz, 2H), 7.38 (t, J=7.3 Hz, 1H),7.41 (d, J=7.3 Hz, 1H), 7.46 (s, 1H), 7.49 (s, 1H), 7.59 (d, J=7.3 Hz,1H), 7.64 (s, 1H), 7.93 (d, J=8.6 Hz, 2H), 8.57 (d, J=5.5 Hz, 1H)

Mass spectrometric value (FD−MS, m/z): 399 (M⁺)

Compound 79 Methyl3-[(6,7-dimethoxy-4-quinolyl)oxy]naphthalene-2-carboxylate

4-Chloro-6,7-dimethoxyquinoline (100 mg), methyl 2-hydroxy-3-naphthoate(271 mg), and 4-dimethylaminopyridine (164 mg) were suspended ino-dichlorobenzene (6 ml), and the suspension was stirred at 150° C. for2 hr. The reaction solution was cooled to room temperature, water wasthen added to the reaction solution, and the mixture was extracted withethyl acetate. The ethyl acetate layer was then washed with water andsaturated brine and was dried over anhydrous sodium sulfate. The solventwas removed therefrom by distillation under the reduced pressure, andthe residue was purified by column chromatography usingacetone-chloroform to give the title compound (7 mg, yield 4%).

¹H-NMR (CDCl₃, 400 MHz): δ 3.57 (s, 3H), 4.01 (s, 6H), 6.28 (d, J=5.4Hz, 1H), 7.46-7.61 (m, 5H), 7.77 (d, J=8.0 Hz, 1H), 7.93 (d, J=8.0 Hz,1H), 8.37 (d, J=5.4 Hz, 1H), 8.59 (s, 1H)

Mass spectrometric value (ESI−MS, m/z): 390 (M+1)⁺

Compound 80 Ethyl 2-[(6,7-dimethoxy-4-quinolyl)oxy]benzoate

4-Chloro-6,7-dimethoxyquinoline (100 mg), ethyl salicylate (336 mg), and4-dimethylaminopyridine (244 mg) were suspended in o-dichlorobenzene (1ml), and the suspension was stirred at 120° C. overnight. The reactionsolution was cooled to room temperature, and the solvent was removed bydistillation under the reduced pressure. Water was then added to theresidue, and the mixture was extracted with chloroform. The chloroformlayer was washed with water and was dried over anhydrous sodium sulfate.The solvent was removed therefrom by distillation under the reducedpressure, and the residue was purified by column chromatography usingacetone-hexane to give the title compound (100 mg, yield 56%).

¹H-NMR (CDCl₃, 400 MHz): δ 0.87 (t, 3H), 4.06 (m, 8H), 6.28 (d, J=5.4Hz, 1H), 7.23-7.42 (m, 3H), 7.64 (m, 2H), 8.07 (dd, J=7.8 Hz, 1.7 Hz,1H), 8.45 (d, J=5.4 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 354 (M+1)⁺

Compound 81 Ethyl 4-chloro-2-[(6,7-dimethoxy-4-quinolyl)oxy]benzoate

4-Chlorosalicylic acid (344 mg),1-ethyl-3-(3-dimethylaminopropylcarbodiimide hydrochloride (420 mg),1-hydroxybenzotriazole hydrate (337 mg), and ethanol (2 ml) weredissolved in N,N-dimethylformamide to prepare a solution which was thenstirred at room temperature overnight. Water was added to the reactionsolution, and the mixture was extracted with ethyl acetate. The ethylacetate layer was then washed with water and was dried over anhydroussodium sulfate. The solvent was removed therefrom by distillation underthe reduced pressure, and the residue was purified by columnchromatography using acetone-hexane to give ethyl 4-chlorosalicylate(174 mg, yield 43%).

Ethyl 4-chlorosalicylate (174 mg), 4-chloro-6,7-dimethoxyquinoline (195mg), and 4-dimethylaminopyridine (320 mg) were suspended ino-dichlorobenzene (1 ml), and the suspension was stirred at 120° C.overnight. The reaction solution was cooled to room temperature, and thesolvent was removed therefrom by distillation under the reducedpressure. Water was then added to the residue, and the mixture wasextracted with chloroform. The chloroform layer was washed with waterand was dried over anhydrous sodium sulfate. The solvent was removedtherefrom by distillation under the reduced pressure, and the residuewas purified by column chromatography using acetone-hexane to give thetitle compound (26 mg, yield 8%).

¹H-NMR (CDCl₃, 400 MHz): δ 0.88 (t, J=7.1 Hz, 3H), 4.06 (m, 8H), 6.31(d, J=5.1 Hz, 1H), 7.26 (d, J=2.0 Hz, 1H), 7.37 (dd, J=8.4 Hz, 2.0 Hz,1H), 7.43 (s, 1H), 7.56 (s, 1H), 8.02 (d, J=8.4 Hz, 1H), 8.48 (d, J=5.1Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 388 (M+1)⁺

Compound 82 Ethyl 2-[(6,7-dimethoxy-4-quinolyl)oxy]-4-methyl benzoate

4-Methylsalicylic acid (304 mg),1-ethyl-3-(3-dimethylaminopropylcarbodiimide hydrochloride (420 mg),1-hydroxybenzotriazole hydrate (337 mg), and ethanol (2 ml) weredissolved in N,N-dimethylformamide to prepare a solution which was thenstirred at room temperature overnight. Water was added to the reactionsolution, and the mixture was extracted with ethyl acetate. The ethylacetate layer was then washed with water and was dried over anhydroussodium sulfate. The solvent was removed therefrom by distillation underthe reduced pressure, and the residue was purified by columnchromatography using acetone-hexane to give ethyl 4-methylsalicylate(175 mg, yield 49%).

Ethyl 4-methylsalicylate (175 mg), 4-chloro-6,7-dimethoxyquinoline (216mg), and 4-dimethylaminopyridine (355 mg) were suspended ino-dichlorobenzene (1 ml), and the suspension was stirred at 120° C.overnight. The reaction solution was cooled to room temperature, and thesolvent was removed by distillation under the reduced pressure. Waterwas then added to the residue, and the mixture was extracted withchloroform. The chloroform layer was washed with water and was driedover anhydrous sodium sulfate. The solvent was removed therefrom bydistillation under the reduced pressure, and the residue was purified bycolumn chromatography using acetone-hexane to give the title compound(28 mg, yield 9%).

¹H-NMR (CDCl₃, 400 MHz): δ 0.84 (t, J=7.1 Hz, 3H), 2.44 (s, 3H), 4.04(m, 8H), 6.27 (d, J=5.4 Hz, 1H), 7.05 (s, 1H), 7.19 (d, J=7.9 Hz, 1H),7.42 (s, 1H), 7.61 (s, 1H), 7.98 (d, J=7.9 Hz, 1H), 8.45 (d, J=5.4 Hz,1H)

Mass spectrometric value (ESI−MS, m/z): 368 (M+1)⁺

Compound 83 Ethyl 2-[(6,7-dimethoxy-4-quinolyl)oxy]-5-fluorobenzoate

5-Fluoro-2-hydroxybenzoic acid (344 mg),1-ethyl-3-(3-dimethylaminopropylcarbodiimide hydrochloride (420 mg),1-hydroxybenzotriazole hydrate (337 mg), and ethanol (2 ml) weredissolved in N,N-dimethylformamide to prepare a solution which was thenstirred at room temperature overnight. Water was added to the reactionsolution, and the mixture was extracted with ethyl acetate. The ethylacetate layer was then washed with water and was dried over anhydroussodium sulfate. The solvent was removed therefrom by distillation underthe reduced pressure, and the residue was purified by columnchromatography using acetone-hexane to give ethyl 5-fluorosalicylate(191 mg, yield 28%).

Ethyl 5-fluorosalicylate (191 mg), 4-chloro-6,7-dimethoxyquinoline (125mg), and 4-dimethylaminopyridine (205 mg) were suspended ino-dichlorobenzene (1 ml), and the suspension was stirred at 120° C.overnight. The reaction solution was cooled to room temperature, and thesolvent was removed by distillation under the reduced pressure. Waterwas then added to the residue, and the mixture was extracted withchloroform. The chloroform layer was washed with water and was driedover anhydrous sodium sulfate. The solvent was removed therefrom bydistillation under the reduced pressure, and the residue was purified bycolumn chromatography using acetone-hexane to give the title compound(64 mg, yield 22%).

¹H-NMR (CDCl₃, 400 MHz): δ 0.87 (t, J=7.1 Hz, 3H), 4.07 (m, 8H), 6.24(d, J=5.3 Hz, 1H), 7.22-7.37 (m, 2H), 7.42 (s, 1H), 7.60 (s, 1H), 7.77(dd, J=5.8 Hz, 3.2 Hz, 1H), 8.46 (d, J=5.3 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 372 (M+1)⁺

Compound 84 Ethyl 5-chloro-2-[(6,7-dimethoxy-4-quinolyl)oxy]benzoate

5-Chlorosalicylic acid (344 mg),1-ethyl-3-(3-dimethylaminopropylcarbodiimide hydrochloride (420 mg),1-hydroxybenzotriazole hydrate (337 mg), and ethanol (2 ml) weredissolved in N,N-dimethylformamide to prepare a solution which was thenstirred at room temperature overnight. Water was added to the reactionsolution, and the mixture was extracted with ethyl acetate. The ethylacetate layer was then washed with water and was dried over anhydroussodium sulfate. The solvent was removed therefrom by distillation underthe reduced pressure, and the residue was purified by columnchromatography using acetone-hexane to give ethyl 5-chlorosalicylate(147 mg, yield 37%).

Ethyl 5-chlorosalicylate (147 mg), 4-chloro-6,7-dimethoxyquinoline (165mg), and 4-dimethylaminopyridine (270 mg) were suspended ino-dichlorobenzene (1 ml), and the suspension was stirred at 120° C.overnight. The reaction solution was cooled to room temperature, and thesolvent was removed by distillation under the reduced pressure. Waterwas then added to the residue, and the mixture was extracted withchloroform. The chloroform layer was washed with water and was driedover anhydrous sodium sulfate. The solvent was removed therefrom bydistillation under the reduced pressure, and the residue was purified bycolumn chromatography using acetone-hexane to give the title compound(41 mg, yield 15%).

¹H-NMR (CDCl₃, 400 MHz): δ 0.90 (t, J=7.1 Hz, 3H), 4.08 (m, 8H), 6.28(d, J=5.8 Hz, 1H), 7.19 (d, J=8.6 Hz, 1H), 7.42 (s, 1H), 7.59 (m, 2H),8.04 (d, J=2.4 Hz, 1H), 8.46 (d, J=5.3 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 388 (M+1)⁺

Compound 85 Ethyl 5-bromo-2-[(6,7-dimethoxy-4-quinolyl)oxy]benzoate

5-Bromosalicylic acid (434 mg),1-ethyl-3-(3-dimethylaminopropylcarbodiimide hydrochloride (420 mg),1-hydroxybenzotriazole hydrate (337 mg), and ethanol (2 ml) weredissolved in N,N-dimethylformamide to prepare a solution which was thenstirred at room temperature overnight. Water was added to the reactionsolution, and the mixture was extracted with ethyl acetate. The ethylacetate layer was then washed with water and was dried over anhydroussodium sulfate. The solvent was removed therefrom by distillation underthe reduced pressure, and the residue was purified by columnchromatography using acetone-hexane to give ethyl 5-bromosalicylate (299mg, yield 61%).

Ethyl 5-bromosalicylate (299 mg), 4-chloro-6,7-dimethoxyquinoline (270mg), and 4-dimethylaminopyridine (440 mg) were suspended ino-dichlorobenzene (1 ml), and the suspension was stirred at 120° C.overnight. The reaction solution was cooled to room temperature, and thesolvent was removed by distillation under the reduced pressure. Waterwas then added to the residue, and the mixture was extracted withchloroform. The chloroform layer was washed with water and was driedover anhydrous sodium sulfate. The solvent was removed therefrom bydistillation under the reduced pressure, and the residue was purified bycolumn chromatography using acetone-hexane to give the title compound(40 mg, yield 8%).

¹H-NMR (CDCl₃, 400 MHz): δ 0.91 (t, J=7.1 Hz, 3H), 4.07 (m, 8H), 6.28(d, J=5.3 Hz, 1H), 7.13 (d, J=8.8 Hz, 1H), 7.43 (s, 1H), 7.57 (s, 1H),7.73 (dd, J=8.8 Hz, 2.4 Hz, 1H), 8.19 (d, J=2.4 Hz, 1H), 8.47 (d, J=5.3Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 432 (M+1)⁺

Compound 86 Ethyl 2-[(6,7-dimethoxy-4-quinolyl)oxy]-5-iodobenzoate

5-Iodosalicylic acid (528 mg),1-ethyl-3-(3-dimethylaminopropylcarbodiimide hydrochloride (420 mg),1-hydroxybenzotriazole hydrate (337 mg), and ethanol (2 ml) weredissolved in N,N-dimethylformamide to prepare a solution which was thenstirred at room temperature overnight. Water was added to the reactionsolution, and the mixture was extracted with ethyl acetate. The ethylacetate layer was then washed with water and was dried over anhydroussodium sulfate. The solvent was removed therefrom by distillation underthe reduced pressure, and the residue was purified by columnchromatography using acetone-hexane to give ethyl 5-iodosalicylate (457mg, yield 78%).

Ethyl 5-iodosalicylate (457 mg), 4-chloro-6,7-dimethoxyquinoline (348mg), and 4-dimethylaminopyridine (573 mg) were suspended ino-dichlorobenzene (1 ml), and the suspension was stirred at 120° C.overnight. The reaction solution was cooled to room temperature, and thesolvent was removed by distillation under the reduced pressure. Waterwas then added to the reaction solution, and the mixture was extractedwith chloroform. The chloroform layer was washed with water and wasdried over anhydrous sodium sulfate. The solvent was removed therefromby distillation under the reduced pressure, and the residue was purifiedby column chromatography using acetone-hexane to give the title compound(31 mg, yield 4%).

¹H-NMR (CDCl₃, 400 MHz): δ 0.90 (t, J=7.1 Hz, 3H), 4.07 (m, 8H), 6.29(d, J=5.3 Hz, 1H), 7.00 (d, J=8.6 Hz, 1H), 7.42 (s, 1H), 7.56 (s, 1H),7.91 (dd, J=8.6 Hz, 2.3 Hz, 1H), 8.36 (d, J=2.3 Hz, 1H), 8.46 (d, J=5.3Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 480 (M+1)⁺

Compound 87 Ethyl 2-[(6,7-dimethoxy-4-quinolyl)oxy]-5-methylbenzoate

4-Chloro-6,7-dimethoxyquinoline (113 mg), ethyl 5-methylsalicylate (632mg), and 4-dimethylaminopyridine (435 mg) were suspended ino-dichlorobenzene (5 ml), and the suspension was stirred at 160° C.overnight. The reaction solution was cooled to room temperature, and thesolvent was then removed therefrom by distillation under the reducedpressure. Chloroform was added to the residue, and the mixture waswashed with a 1 N aqueous sodium hydroxide solution and saturated brineand was dried over anhydrous magnesium sulfate. The solvent was removedtherefrom by distillation under the reduced pressure, and the residuewas purified by column chromatography using chloroform and by thin layerchromatography using acetone-hexane to give the title compound (64.1 mg,yield 35%).

¹H-NMR (CDCl₃, 400 MHz): δ 0.84 (t, J=7.1 Hz, 3H), 2.45 (s, 3H), 4.04(m, 2H), 4.05 (s, 3H), 4.06 (s, 3H), 6.26 (d, J=5.4 Hz, 1H), 7.14 (d,J=8.3 Hz, 1H), 7.42 (s, 1H), 7.41-7.44 (m, 1H), 7.63 (s, 1H), 7.87 (d,J=1.4 Hz, 1H), 8.44 (d, J=5.4 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 368 (M+1)⁺

Compound 88 Ethyl 5-acetyl-2-[(6,7-dimethoxy-4-quinolyl)oxy]benzoate

5-Acetylsalicylic acid (200 mg),1-ethyl-3-(3-dimethylaminopropylcarbodiimide hydrochloride (382 mg),1-hydroxybenzotriazole hydrate (306 mg), and ethanol (2 ml) weredissolved in N,N-dimethylformamide to prepare a solution which was thenstirred at room temperature overnight. Water was added to the reactionsolution, and the mixture was extracted with ethyl acetate. The ethylacetate layer was then washed with water and was dried over anhydroussodium sulfate. The solvent was removed therefrom by distillation underthe reduced pressure, and the residue was purified by columnchromatography using acetone-hexane to give ethyl 5-acetylsalicylate(211 mg, yield 92%).

Ethyl 5-acetylsalicylate (211 mg), 4-chloro-6,7-dimethoxyquinoline (111mg), and 4-dimethylaminopyridine (183 mg) were suspended ino-dichlorobenzene (1 ml), and the suspension was stirred at 120° C.overnight. The reaction solution was cooled to room temperature, and thesolvent was removed by distillation under the reduced pressure. Waterwas then added to the residue, and the mixture was extracted withchloroform. The chloroform layer was washed with water and was driedover anhydrous sodium sulfate. The solvent was removed therefrom bydistillation under the reduced pressure, and the residue was purified bycolumn chromatography using acetone-hexane to give the title compound(19 mg, yield 5%).

¹H-NMR (CDCl₃, 400 MHz): δ 0.97 (t, J=7.1 Hz, 3H), 2.68 (s, 3H), 4.04(s, 3H), 4.06 (s, 3H), 4.14 (q, J=7.1 Hz, 2H), 6.37 (d, J=5.2 Hz, 1H),7.28 (d, J=8.5 Hz, 1H), 7.44 (s, 1H), 7.55 (s, 1H), 8.20 (dd, J=8.5 Hz,2.2 Hz, 1H), 8.50 (d, J=5.2 Hz, 1H), 8.62 (d, J=2.2 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 396 (M+1)⁺

Compound 89 Ethyl2-[(6,7-dimethoxy-4-quinolyl)oxy]-5-(2,4-difluorophenyl)benzoate

Diflunisal (250 mg), 1-ethyl-3-(3-dimethylaminopropylcarbodiimidehydrochloride (382 mg), 1-hydroxybenzotriazole hydrate (306 mg), andethanol (2 ml) were dissolved in N,N-dimethylformamide to prepare asolution which was then stirred at room temperature overnight. Water wasadded to the reaction solution, and the mixture was extracted with ethylacetate. The ethyl acetate layer was then washed with water and wasdried over anhydrous sodium sulfate. The solvent was removed therefromby distillation under the reduced pressure, and the residue was purifiedby column chromatography using acetone-hexane to give ethyl5-(2,4-difluorophenyl)salicylate (188 mg, yield 34%).

Ethyl 5-(2,4-difluorophenyl)salicylate (188 mg),4-chloro-6,7-dimethoxyquinoline (57 mg), and 4-dimethylaminopyridine (93mg) were suspended in o-dichlorobenzene (1 ml), and the suspension wasstirred at 120° C. overnight. The reaction solution was cooled to roomtemperature, and the solvent was removed by distillation under thereduced pressure. Water was then added to the reaction solution, and themixture was extracted with chloroform. The chloroform layer was washedwith water and was dried over anhydrous sodium sulfate. The solvent wasremoved therefrom by distillation under the reduced pressure. Theresidue was purified by column chromatography using acetone-hexane togive the title compound (13 mg, yield 24%).

¹H-NMR (CDCl₃, 400 MHz): δ 0.89 (t, J=7.3 Hz, 3H), 4.09 (m, 8H), 6.38(d, J=5.3 Hz, 1H), 6.99 (m, 2H), 7.31 (d, J=8.6 Hz, 1H), 7.44-7.51 (m,2H), 7.62 (s, 1H), 7.77 (m, 1H), 8.18 (m, 1H), 8.49 (d, J=5.3 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 466 (M+1)⁺

Compound 90 Ethyl2-[(6,7-dimethoxy-4-quinolyl)oxy]-5-(pyrrol-1-yl)benzoate

2-Hydroxy-5-(pyrrol-1-yl)benzoic acid (406 mg),1-ethyl-3-(3-dimethylaminopropylcarbodiimide hydrochloride (420 mg),1-hydroxybenzotriazole hydrate (337 mg), and ethanol (2 ml) weredissolved in N,N-dimethylformamide to prepare a solution which was thenstirred at room temperature overnight. Water was added to the reactionsolution, and the mixture was extracted with ethyl acetate. The ethylacetate layer was then washed with water and was dried over anhydroussodium sulfate. The solvent was removed therefrom by distillation underthe reduced pressure, and the residue was purified by columnchromatography using acetone-hexane to give ethyl5-(pyrrol-1-yl)salicylate (170 mg, yield 20%).

Ethyl 5-(pyrrol-1-yl)salicylate (170 mg),4-chloro-6,7-dimethoxyquinoline (87 mg), and 4-dimethylaminopyridine(143 mg) were suspended in o-dichlorobenzene (1 ml), and the suspensionwas stirred at 120° C. overnight. The reaction solution was cooled toroom temperature, and the solvent was removed by distillation under thereduced pressure. Water was then added to the residue, and the mixturewas extracted with chloroform. The chloroform layer was washed withwater and was dried over anhydrous sodium sulfate. The solvent wasremoved therefrom by distillation under the reduced pressure, and theresidue was purified by column chromatography using acetone-hexane togive the title compound (36 mg, yield 15%).

¹H-NMR (CDCl₃, 400 MHz): δ 0.87 (t, J=7.3 Hz, 3H), 4.09 (m, 8H), 6.32(d, J=5.4 Hz, 1H), 6.4 (t, J=2.2 Hz, 2H), 7.15 (t, J=2.2 Hz, 2H), 7.31(d, J=8.7 Hz, 1H), 7.43 (s, 1H), 7.61 (s, 1H), 7.64 (dd, J=8.7 Hz, 3.0Hz, 1H), 8.09 (d, J=3.0 Hz, 1H), 8.47 (d, J=5.4 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 419 (M+1)⁺

Compound 91 Ethyl 2-[(6,7-dimethoxy-4-quinolyl)oxy]-5-methoxybenzoate

5-Methoxysalicylic acid (2.00 g) was suspended in ethanol (28 ml), andthionyl chloride (2.11 g) was gradually added dropwise to thesuspension. Thereafter, the mixture was heated under reflux for 2 hr.The solvent was removed therefrom by distillation under the reducedpressure. Water was added to the residue, and the mixture wasneutralized with a 20% aqueous sodium hydroxide solution and was thenextracted with chloroform. The chloroform layer was then washed withwater and saturated brine and was dried over anhydrous sodium sulfate.The solvent was removed therefrom by distillation under the reducedpressure, and the residue was purified by column chromatography usingacetone-hexane to give ethyl 5-methoxysalicylic acid (1.37 g, yield58%).

4-Chloro-6,7-dimethoxyquinoline (514 mg), ethyl 5-methoxysalicylic acid(1.35 g), and 4-dimethylaminopyridine (843 mg) were suspended ino-dichlorobenzene (8 ml), and the suspension was stirred at 180° C. for4 hr. The reaction solution was cooled to room temperature, water wasthen added to the reaction solution, and the mixture was extracted withethyl acetate. The ethyl acetate layer was then washed with water andsaturated brine and was dried over anhydrous sodium sulfate. The solventwas removed therefrom by distillation under the reduced pressure, andthe residue was purified by column chromatography using acetone-hexaneto give the title compound (152 mg, yield 17%).

¹H-NMR (CDCl₃, 400 MHz): δ 0.73 (t, J=7.2 Hz, 3H), 3.82 (s, 3H),3.94-3.98 (m, 8H), 6.17 (d, J=5.2 Hz, 1H), 7.10 (m, 2H), 7.38 (s, 1H),7.49 (s, 1H), 7.54 (s, 1H), 8.36 (d, J=5.2 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 384 (M+1)⁺

Compound 92 Ethyl 2-[(6,7-dimethoxy-4-quinolyl)oxy]-6-methyl benzoate

4-Chloro-6,7-dimethoxyquinoline (112 mg), ethyl 6-methylsalicylate (360mg), and 4-dimethylaminopyridine (244 mg) were suspended ino-dichlorobenzene (1 ml), and the suspension was stirred at 120° C.overnight and was further stirred at 140° C. for 2 hr. The reactionsolution was cooled to room temperature, and the solvent was removed bydistillation under the reduced pressure. Water was then added to theresidue, and the mixture was extracted with chloroform. The chloroformlayer was washed with water and was dried over anhydrous sodium sulfate.The solvent was removed therefrom by distillation under the reducedpressure, and the residue was purified by column chromatography usingacetone-hexane to give the title compound (168 mg, yield 91%).

¹H-NMR (CDCl₃, 400 MHz): δ 0.96 (t, J=7.1 Hz, 3H), 2.44 (s, 3H), 4.03(s, 3H), 4.05 (s, 3H), 4.10 (q, J=7.1 Hz, 2H), 6.50 (d, J=5.2 Hz, 1H),6.99 (d, J=7.9 Hz, 1H), 7.15 (d, J=7.9 Hz, 1H), 7.37 (t, J=7.9 Hz, 1H),7.42 (s, 1H), 7.52 (s, 1H), 8.50 (d, J=5.2 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 368 (M+1)⁺

Compound 93 Isopropyl 2-[(6,7-dimethoxy-4-quinolyl)oxy]benzoate

4-Chloro-6,7-dimethoxyquinoline (112 mg), isopropyl salicylate (360 mg),and 4-dimethylaminopyridine (244 mg) were suspended in o-dichlorobenzene(1 ml), and the suspension was stirred at 120° C. overnight. Thereaction solution was cooled to room temperature, and the solvent wasremoved by distillation under the reduced pressure. Water was then addedto the residue, and the mixture was extracted with chloroform. Thechloroform layer was washed with water and was dried over anhydroussodium sulfate. The solvent was removed therefrom by distillation underthe reduced pressure, and the residue was purified by columnchromatography using acetone-hexane to give the title compound (38 mg,yield 21%).

¹H-NMR (CDCl₃, 400 MHz): δ 0.84 (m, 6H), 4.06 (m, 6H), 5.00 (m, 1H),6.25 (d, J=5.4 Hz, 1H), 7.27 (m, 1H), 7.41 (m, 2H), 7.64 (m, 2H), 8.07(m, 1H), 8.44 (d, J=5.4 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 368 (M+1)⁺

Compound 94 Propyl 2-[(6,7-dimethoxy-4-quinolyl)oxy]benzoate

4-Chloro-6,7-dimethoxyquinoline (112 mg), n-propyl salicylate (360 mg),and 4-dimethylaminopyridine (244 mg) were suspended in o-dichlorobenzene(1 ml), and the suspension was stirred at 120° C. overnight and at 140°C. for 2 hr. The reaction solution was cooled to room temperature, andthe solvent was removed by distillation under the reduced pressure.Water was then added to the reaction solution, and the mixture wasextracted with chloroform. The chloroform layer was washed with waterand was dried over anhydrous sodium sulfate. The solvent was removedtherefrom by distillation under the reduced pressure, and the residuewas purified by column chromatography using acetone-hexane to give thetitle compound (104 mg, yield 57%).

¹H-NMR (CDCl₃, 400 MHz): δ 0.67 (t, J=7.6 Hz, 3H), 1.30 (m, 2H), 4.00(t, J=6.6 Hz, 2H), 4.05 (s, 3H), 4.06 (s, 3H), 6.29 (d, J=5.1 Hz, 1H),7.23 (dd, J=8.3 Hz, 1.0 Hz, 1H), 7.39 (td, J=7.8 Hz, 1.0 Hz, 1H), 7.42(s, 1H), 7.63 (m, 2H), 8.08 (dd, J=7.8 Hz, 1.7 Hz, 1H), 8.46 (d, J=5.1Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 368 (M+1)⁺

Compound 95 Propyl 2-[(6,7-dimethoxy-4-quinolyl)oxy]-5-acetyl benzoate

5-Acetylsalicylic acid (360 mg),1-ethyl-3-(3-dimethylaminopropylcarbodiimide hydrochloride (458 mg),1-hydroxybenzotriazole hydrate (36.7 mg), and propanol (2 ml) weredissolved in N,N-dimethylformamide to prepare a solution which was thenstirred at room temperature overnight. Water was added to the reactionsolution, and the mixture was extracted with ethyl acetate. The ethylacetate layer was then washed with water and was dried over anhydroussodium sulfate. The solvent was removed therefrom by distillation underthe reduced pressure, and the residue was purified by columnchromatography using acetone-hexane to give propyl 5-acetylsalicylate(202 mg, yield 45%).

Propyl 5-acetylsalicylate (202 mg), 4-chloro-6,7-dimethoxyquinoline (101mg), and 4-dimethylaminopyridine (164 mg) were suspended ino-dichlorobenzene (1 ml), and the suspension was stirred at 120° C.overnight. The reaction solution was cooled to room temperature, and thesolvent was removed by distillation under the reduced pressure. Waterwas then added to the residue, and the mixture was extracted withchloroform. The chloroform layer was washed with water and was driedover anhydrous sodium sulfate. The solvent was removed therefrom bydistillation under the reduced pressure. The residue was purified bycolumn chromatography using acetone-hexane to give the title compound(35 mg, yield 9%).

¹H-NMR (CDCl₃, 400 MHz): δ 0.73 (t, J=7.3 Hz, 3H), 1.39 (m, 2H), 2.68(s, 3H), 4.07 (m, 8H), 6.39 (d, J=5.4 Hz, 1H), 7.26 (d, J=8.5 Hz, 1H),7.44 (s, 1H), 7.54 (s, 1H), 8.19 (dd, J=8.5 Hz, 2.3 Hz, 1H), 8.50 (d,J=5.4 Hz, 1H), 8.62 (d, J=2.3 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 410 (M+1)⁺

Compound 96 Propyl2-[(6,7-dimethoxy-4-quinolyl)oxy]-5-(2,4-difluorophenyl)benzoate

Diflunisal (500 mg), 1-ethyl-3-(3-dimethylaminopropylcarbodiimidehydrochloride (458 mg), 1-hydroxybenzotriazole hydrate (36.7 mg), andpropanol (2 ml) were dissolved in N,N-dimethylformamide to prepare asolution which was then stirred at room temperature overnight. Water wasadded to the reaction solution, and the mixture was extracted with ethylacetate. The ethyl acetate layer was then washed with water and wasdried over anhydrous sodium sulfate. The solvent was removed therefromby distillation under the reduced pressure, and the residue was purifiedby column chromatography using acetone-hexane to give propyl5-(2,4-difluorophenyl)salicylate (179 mg, yield 30%).

Propyl 5-(2,4-difluorophenyl)salicylate (179 mg),4-chloro-6,7-dimethoxyquinoline (70 mg), and 4-dimethylaminopyridine(110 mg) were suspended in o-dichlorobenzene (1 ml), and the suspensionwas stirred at 120° C. overnight. The reaction solution was cooled toroom temperature, and the solvent was removed by distillation under thereduced pressure. Water was then added to the residue, and the mixturewas extracted with chloroform. The chloroform layer was washed withwater and was dried over anhydrous sodium sulfate. The solvent wasremoved therefrom by distillation under the reduced pressure, and theresidue was purified by column chromatography using acetone-hexane togive the title compound (30 mg, yield 10%).

¹H-NMR (CDCl₃, 400 MHz): δ 0.67 (t, J=7.3 Hz, 3H), 1.31 (m, 2H), 4.04(m, 8H), 6.40 (d, J=5.2 Hz, 1H), 6.99 (m, 2H), 7.30 (d, J=8.3 Hz, 1H),7.47 (m, 2H), 7.61 (s, 1H), 7.76 (m, 1H), 8.19 (m, 1H), 8.49 (d, J=5.2Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 480 (M+1)⁺

Compound 97 Isobutyl 2-[(6,7-dimethoxy-4-quinolyl)oxy]benzoate

4-Chloro-6,7-dimethoxyquinoline (100 mg), isobutyl salicylate (388 mg),and 4-dimethylaminopyridine (244 mg) were suspended in o-dichlorobenzene(1 ml), and the suspension was stirred at 120° C. overnight and at 140°C. for 3 hr. The reaction solution was cooled to room temperature, andthe solvent was removed by distillation under the reduced pressure.Water was then added to the residue, and the mixture was extracted withchloroform. The chloroform layer was washed with water and was driedover anhydrous sodium sulfate. The solvent was removed therefrom bydistillation under the reduced pressure, and the residue was purified bycolumn chromatography using acetone-hexane to give the title compound(47 mg, yield 25%).

¹H-NMR (CDCl₃, 400 MHz): δ 0.67 (m, 6H), 1.59 (m, 1H), 3.83 (m, 2H),4.02 (m, 6H), 6.28 (m, 1H), 7.14-7.64 (m, 5H), 8.05 (m, 1H), 8.43 (m,1H)

Mass spectrometric value (ESI−MS, m/z): 382 (M+1)⁺

Compound 98 Butyl 2-[(6,7-dimethoxy-4-quinolyl)oxy]benzoate

4-Chloro-6,7-dimethoxyquinoline (100 mg), butyl salicylate (388 mg), and4-dimethylaminopyridine (244 mg) were suspended in o-dichlorobenzene (1ml), and the suspension was stirred at 120° C. overnight and at 140° C.for 3 hr. The reaction solution was cooled to room temperature, and thesolvent was removed by distillation under the reduced pressure. Waterwas then added to the residue, and the mixture was extracted withchloroform. The chloroform layer was washed with water and was driedover anhydrous sodium sulfate. The solvent was removed therefrom bydistillation under the reduced pressure, and the residue was purified bycolumn chromatography using acetone-hexane to give the title compound(106 mg, yield 57%).

¹H-NMR (CDCl₃, 400 MHz): δ 0.66 (t, J=7.3 Hz, 3H), 1.06 (m, 2H), 1.24(m, 2H), 4.03 (m, 8H), 6.28 (d, J=5.3 Hz, 1H), 7.23 (d, J=8.0 Hz, 1H),7.37-7.43 (m, 2H), 7.63 (m, 2H), 8.07 (dd, J=7.8 Hz, 1.4 Hz, 1H), 8.45(d, J=5.3 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 382 (M+1)⁺

Compound 99 Isoamyl 2-[(6,7-dimethoxy-4-quinolyl)oxy]benzoate

4-Chloro-6,7-dimethoxyquinoline (100 mg), isoamyl salicylate (416 mg),and 4-dimethylaminopyridine (244 mg) were suspended in o-dichlorobenzene(1 ml), and the suspension was stirred at 120° C. overnight and at 140°C. for 3 hr. The reaction solution was cooled to room temperature, andthe solvent was removed by distillation under the reduced pressure.Water was then added to the residue, and the mixture was extracted withchloroform. The chloroform layer was washed with water and was driedover anhydrous sodium sulfate. The solvent was removed therefrom bydistillation under the reduced pressure, and the residue was purified bycolumn chromatography using acetone-hexane to give the title compound(110 mg, yield 56%).

¹H-NMR (CDCl₃, 400 MHz): δ 0.67 (m, 6H), 1.13 (m, 2H), 1.34 (m, 1H),4.06 (m, 8H), 6.29 (d, J=5.2 Hz, 1H), 7.23 (m, 1H), 7.40 (m, 2H), 7.62(m, 2H), 8.07 (m, 1H), 8.46 (d, J=5.2 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 396 (M+1)⁺

Compound 100 (Z)-3-Hexenyl 2-[(6,7-dimethoxy-4-quinolyl)oxy]benzoate

4-Chloro-6,7-dimethoxyquinoline (112 mg), (Z)-3-hexenyl salicylate (440mg), and 4-dimethylaminopyridine (244 mg) were suspended ino-dichlorobenzene (1 ml), and the suspension was stirred at 120° C.overnight. The reaction solution was cooled to room temperature, and thesolvent was removed by distillation under the reduced pressure. Waterwas then added to the residue, and the mixture was extracted withchloroform. The chloroform layer was washed with water and was driedover anhydrous sodium sulfate. The solvent was removed therefrom bydistillation under the reduced pressure, and the residue was purified bycolumn chromatography using acetone-hexane to give the title compound(130 mg, yield 64%).

¹H-NMR (CDCl₃, 400 MHz): δ 0.86 (t, J=7.6 Hz, 3H), 1.82 (m, 2H), 2.00(m, 2H), 4.00 (t, J=7.1 Hz, 2H), 4.05 (s, 3H), 4.06 (s, 3H), 5.03 (m,1H), 5.30 (m, 1H), 6.28 (d, J=5.1 Hz, 1H), 7.23 (m, 1H), 7.40 (m, 2H),7.63 (m, 2H), 8.07 (dd, J=7.8 Hz, 1.7 Hz, 1H), 8.45 (d, J=5.1 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 408 (M+1)⁺

Compound 101 2-Ethylhexyl 2-[(6,7-dimethoxy-4-quinolyl)oxy]benzoate

4-Chloro-6,7-dimethoxyquinoline (100 mg), 2-ethylhexylsalicylate (500mg), and 4-dimethylaminopyridine (244 mg) were suspended ino-dichlorobenzene (1 ml), and the suspension was stirred at 120° C.overnight and at 140° C. for 3 hr. The reaction solution was cooled toroom temperature, and the solvent was removed by distillation under thereduced pressure. Water was then added to the residue, and the mixturewas extracted with chloroform. The chloroform layer was washed withwater and was dried over anhydrous sodium sulfate. The solvent wasremoved therefrom by distillation under the reduced pressure, and theresidue was purified by column chromatography using acetone-hexane togive the title compound (38 mg, yield 18%).

¹H-NMR (CDCl₃, 400 MHz): δ 0.64 (t, J=7.3 Hz, 3H), 0.79 (t, J=6.8 Hz,3H), 1.07 (m, 8H), 1.25 (m, 1H), 4.02 (s, 8H), 6.31 (d, J=5.2 Hz, 1H),7.20 (m, 1H), 7.39 (m, 2H), 7.61 (m, 2H), 8.06 (dd, J=7.8 Hz, 1.7 Hz,1H), 8.46 (d, J=5.2 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 438 (M+1)⁺

Compound 102 Phenyl3-[(6,7-dimethoxy-4-quinolyl)oxy]naphthalene-2-carboxylate

4-Chloro-6,7-dimethoxyquinoline (100 mg), 3-phenyl 2-hydroxynaphthoate(354 mg), and 4-dimethylaminopyridine (164 mg) were suspended ino-dichlorobenzene (5 ml), and the suspension was stirred at 150° C. for2 hr. The reaction solution was cooled to room temperature, water wasthen added to the reaction solution, and the mixture was extracted withethyl acetate. The ethyl acetate layer was then washed with water andsaturated brine and was dried over anhydrous sodium sulfate. The solventwas removed therefrom by distillation under the reduced pressure, andthe residue was purified by column chromatography usingacetone-chloroform to give the title compound (45 mg, yield 22%).

¹H-NMR (CDCl₃, 400 MHz): δ 3.89 (s, 3H), 3.92 (s, 3H), 6.35 (d, J=5.2Hz, 1H), 6.73 (d, J=7.8 Hz, 2H), 7.05-7.18 (m, 3H), 7.34 (s, 1H),7.52-7.62 (m, 3H), 7.66 (s, 1H), 7.78 (d, J=8.0 Hz, 1H), 7.96 (d, J=8.0Hz, 1H), 8.40 (d, J=5.2 Hz, 1H), 8.73 (s, 1H)

Mass spectrometric value (ESI−MS, m/z): 452 (M+1)⁺

Compound 103 Benzyl 2-[(6,7-dimethoxy-4-quinolyl)oxy]benzoate

4-Chloro-6,7-dimethoxyquinoline (100 mg), benzylsalicylate (456 mg), and4-dimethylaminopyridine (244 mg) were suspended in o-dichlorobenzene (1ml), and the suspension was stirred at 120° C. overnight. The reactionsolution was cooled to room temperature, and the solvent was removed bydistillation under the reduced pressure. Water was then added to theresidue, and the mixture was extracted with chloroform. The chloroformlayer was washed with water and was dried over anhydrous sodium sulfate.The solvent was removed therefrom by distillation under the reducedpressure, and the residue was purified by column chromatography usingacetone-hexane to give the title compound (68 mg, yield 33%).

¹H-NMR (CDCl₃, 400 MHz): δ 3.93 (s, 3H), 4.09 (s, 3H), 5.02 (s, 2H),6.28 (d, J=5.5 Hz, 1H), 6.92 (m, 2H), 7.06-7.24 (m, 4H), 7.35-7.45 (m,2H), 7.57 (s, 1H), 7.65 (td, J=7.6, 1.7 Hz, 1H), 8.14 (dd, J=7.8 Hz, 1.7Hz, 1H), 8.47 (d, J=5.5 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 416 (M+1)⁺

Compound 104 N-Phenyl-2-[(6,7-dimethoxy-4-quinolyl)oxy]benzamide

4-Chloro-6,7-dimethoxyquinoline (56 mg), salicylanilide (213 mg), and4-dimethylaminopyridine (122 mg) were suspended in o-dichlorobenzene (1ml), and the suspension was stirred at 140° C. for 4 hr. The reactionsolution was cooled to room temperature, and the solvent was removed bydistillation under the reduced pressure. Water was then added to theresidue, and the mixture was extracted with chloroform. The chloroformlayer was washed with water and was dried over anhydrous sodium sulfate.The solvent was removed therefrom by distillation under the reducedpressure, and the residue was purified by thin layer chromatographyusing acetone-hexane to give the title compound (86 mg, yield 86%).

¹H-NMR (CDCl₃, 400 MHz): δ 3.82 (s, 3H), 4.02 (s, 3H), 6.41 (m, 1H),6.98 (m, 2H), 7.06 (d, J=4.9 Hz, 1H), 7.09 (s, 1H), 7.18-7.28 (m, 4H),7.33-7.38 (m, 2H), 7.45 (s, 1H), 8.66 (d, J=4.9 Hz, 1H), 10.50 (s, 1H)

Mass spectrometric value (ESI−MS, m/z): 399 (M−1)⁻

Compound 105N-Phenyl-5-chloro-2-[(6,7-dimethoxy-4-quinolyl)oxy]-benzamide

4-Chloro-6,7-dimethoxyquinoline (100 mg), 4′-chloro-salicylanilide (445mg), and 4-dimethylaminopyridine (220 mg) were suspended ino-dichlorobenzene (1 ml), and the suspension was stirred at 140° C. for4 hr. The reaction solution was cooled to room temperature, and thesolvent was removed by distillation under the reduced pressure. Waterwas then added to the residue, and the mixture was extracted withchloroform. The chloroform layer was washed with water and was driedover anhydrous sodium sulfate. The solvent was removed therefrom bydistillation under the reduced pressure, and the residue was purified bycolumn chromatography using acetone-hexane to give the title compound(38 mg, yield 20%).

¹H-NMR (CDCl₃, 400 MHz): δ 3.85 (s, 3H), 4.02 (s, 3H), 6.90-7.45 (m,11H), 8.69 (d, J=4.6 Hz, 1H), 10.46 (s, 1H)

Mass spectrometric value (ESI−MS, m/z): 433 (M−1)⁻

Compound 106 5-Chloro-2-[(6,7-dimethoxy-4-quinolyl)oxy]benzamide

4-Chloro-6,7-dimethoxyquinoline (100 mg), 5-chloro-2-hydroxybenzamide(343 mg), and 4-dimethylaminopyridine (244 mg) were suspended ino-dichlorobenzene (1 ml), and the suspension was stirred at 120° C.overnight. The reaction solution was cooled to room temperature, and thesolvent was removed therefrom by distillation under the reducedpressure. The residue was purified by column chromatography usingacetone-hexane to give the title compound (265 mg, yield 100%).

¹H-NMR (CDCl₃, 400 MHz): δ 3.68 (s, 3H), 3.86 (s, 3H), 6.22-6.61 (m,1H), 6.97 (d, J=8.8 Hz, 1H), 7.23 (dd, J=8.8 Hz, 2.7 Hz, 1H), 7.31 (s,1H), 7.44 (s, 1H), 8.10 (m, 1H), 8.20 (d, J=2.7 Hz, 1H), 8.58-8.62 (m,2H)

Mass spectrometric value (ESI−MS, m/z): 359 (M+1)⁺

Compound 107N-(3,4-Dichlorophenyl)-5-chloro-2-[(6,7-dimethoxy-4-quinolyl)oxy]benzamide

4-Chloro-6,7-dimethoxyquinoline (116 mg),3′,4′,5-trichlorosalicylanilide (632 mg), and 4-dimethylaminopyridine(244 mg) were suspended in o-dichlorobenzene (1 ml), and the suspensionwas stirred at 120° C. overnight. The reaction solution was cooled toroom temperature, and the solvent was removed by distillation under thereduced pressure. Water was then added to the residue, and the mixturewas extracted with chloroform. The chloroform layer was washed withwater and was dried over anhydrous sodium sulfate. The solvent wasremoved therefrom by distillation under the reduced pressure, and theresidue was purified by column chromatography using acetone-hexane togive the title compound (14 mg, yield 6%).

¹H-NMR (CDCl₃, 400 MHz): δ 3.87 (s, 3H), 4.03 (s, 3H), 6.88-7.49 (m,9H), 8.70 (d, J=4.9 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 502 (M−1)⁻

Compound 108N-(4-Chlorophenyl)-5-bromo-2-[(6,7-dimethoxy-4-quinolyl)oxy]benzamide

4-Chloro-6,7-dimethoxyquinoline (100 mg),5-bromo-4′-chlorosalicylanilide (653 mg), and 4-dimethylaminopyridine(244 mg) were suspended in o-dichlorobenzene (1 ml), and the suspensionwas stirred at 120° C. overnight. The reaction solution was cooled toroom temperature, and the solvent was removed by distillation under thereduced pressure. Water was then added to the residue, and the mixturewas extracted with chloroform. The chloroform layer was washed withwater and was dried over anhydrous sodium sulfate. The solvent wasremoved therefrom by distillation under the reduced pressure, and theresidue was purified by column chromatography using acetone-hexane togive the title compound (59 mg, yield 23%).

¹H-NMR (CDCl₃, 400 MHz): δ 3.85 (s, 3H), 4.02 (s, 3H), 6.83 (d, J=5.1Hz, 1H), 6.99-7.47 (m, 9H), 8.68 (d, J=4.9 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 513 (M−1)⁻

Compound 109{2-[(6,7-Dimethoxy-4-quinolyl)oxy]-5-methylphenyl}-(piperidino)methanone

2-[(6,7-Dimethoxy-4-quinolyl)oxy]-5-methylbenzoic acid (80 mg) wasdissolved in a 20% thionyl chloride/dichloromethane mixed solvent (3ml), and the solution was heated under reflux overnight. The solvent wasremoved therefrom by distillation under the reduced pressure.1,4-Dioxane (3 ml) was added to the residue, a solution of piperidine(201 mg) in a 2 N aqueous sodium hydroxide solution (3 ml) was addeddropwise thereto, and the mixture was stirred at room temperatureovernight. Water was added to the reaction solution, and the mixture wasextracted with ethyl acetate. The ethyl acetate layer was then washedwith water and saturated brine and was dried over anhydrous sodiumsulfate. The solvent was removed therefrom by distillation under thereduced pressure, and the residue was purified by column chromatographyusing acetone-hexane to give the title compound (58 mg, yield 61%).

¹H-NMR (CDCl₃, 400 MHz): δ 1.27-1.50 (m, 6H), 2.35 (s, 3H), 3.18-3.43(m, 4H), 3.94 (s, 3H), 3.96 (s, 3H), 6.48 (d, J=5.2 Hz, 1H), 6.96 (d,J=8.2 Hz, 1H), 7.17 (m, 2H), 7.34 (s, 1H), 7.47 (s, 1H), 8.41 (d, J=5.2Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 429 (M+Na)⁺

Compound 110N-Methyl-2-[(6,7-dimethoxy-4-quinolyl)oxy]-5-methoxybenzamide

2-[(6,7-Dimethoxy-4-quinolyl)oxy]-5-methoxybenzoic acid (intermediate 2)(74 mg) was dissolved in a 20% thionyl chloride/dichloromethane mixedsolvent (3 ml), and the solution was heated under reflux overnight. Thesolvent was removed therefrom by distillation under the reducedpressure. 1,4-Dioxane (3 ml) was added to the residue, a solution ofmonomethyl ammonium chloride (425 mg) in a 2 N aqueous sodium hydroxidesolution (3 ml) was added dropwise thereto, and the mixture was stirredat room temperature overnight. Water was added to the reaction solution,and the mixture was extracted with ethyl acetate. The ethyl acetatelayer was then washed with water and saturated brine and was dried overanhydrous sodium sulfate. The solvent was removed therefrom bydistillation under the reduced pressure, and the residue was purified bycolumn chromatography using acetone-hexane to give the title compound(33 mg, yield 43%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.78 (s, 3H), 3.81 (s, 3H), 3.97 (s, 3H),3.98 (s, 3H), 6.38 (d, J=5.2 Hz, 1H), 6.91-7.05 (m, 3H), 7.38 (s, 1H),7.42 (s, 1H), 7.64 (d, J=2.8 Hz, 1H), 8.43 (d, J=5.2 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 369 (M+1)⁺

Compound 111N-Isopropyl-2-[(6,7-dimethoxy-4-quinolyl)oxy]-5-methoxybenzamide

2-[(6,7-Dimethoxyquinolyl)oxy]-5-methoxybenzoic acid (74 mg) wasdissolved in a 20% thionyl chloride/dichloromethane mixed solvent (3ml), and the solution was heated under reflux overnight. The solvent wasremoved therefrom by distillation under the reduced pressure.1,4-Dioxane (3 ml) was added to the residue, a solution of isopropylammonium chloride (514 mg) in a 2 N aqueous sodium hydroxide solution (3ml) was added dropwise thereto, and the mixture was stirred at roomtemperature overnight. Water was added to the reaction solution, and themixture was extracted with ethyl acetate. The ethyl acetate layer wasthen washed with water and saturated brine and was dried over anhydroussodium sulfate. The solvent was removed therefrom by distillation underthe reduced pressure, and the residue was purified by columnchromatography using acetone-hexane to give the title compound (57 mg,yield 71%).

¹H-NMR (CDCl₃, 400 MHz): δ 0.74 (d, J=6.0 Hz, 6H), 3.82 (s, 3H), 3.98(m, 7H), 6.28 (d, J=5.2 Hz, 1H), 6.74 (brs, 1H), 7.01 (s, 1H), 7.41 (s,1H), 7.49 (s, 1H), 7.63 (s, 1H), 8.41 (d, J=5.2 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 397 (M+1)⁺

Compound 112N-Cyclohexyl-2-[(6,7-dimethoxy-4-quinolyl)oxy]-5-methoxybenzamide

2-[(6,7-Dimethoxyquinolyl)oxy]-5-methoxybenzoic acid (74 mg) wasdissolved in a 20% thionyl chloride/dichloromethane mixed solvent (3ml), and the solution was heated under reflux overnight. The solvent wasremoved therefrom by distillation under the reduced pressure.1,4-Dioxane (3 ml) was added to the residue, a solution ofcyclohexylamine (208 mg) in a 2 N aqueous sodium hydroxide solution (3ml) was added dropwise thereto, and the mixture was stirred at roomtemperature overnight. Water was added to the reaction solution, and themixture was extracted with ethyl acetate. The ethyl acetate layer wasthen washed with water and saturated brine and was dried over anhydroussodium sulfate. The solvent was removed therefrom by distillation underthe reduced pressure, and the residue was purified by columnchromatography using acetone-hexane to give the title compound (27 mg,yield 29%).

¹H-NMR (CDCl₃, 400 MHz): δ 0.65-0.73 (m, 2H), 0.80-0.89 (m, 1H),1.08-1.18 (m, 2H), 1.32-1.40 (m, 3H), 1.53-1.57 (m, 2H), 3.67-3.78 (m,1H), 3.82 (s, 3H), 4.02 (s, 6H), 6.30 (d, J=5.2 Hz, 1H), 6.85 (brs, 1H),6.99 (m, 2H), 7.38 (s, 1H), 7.47 (s, 1H), 7.62 (s, 1H), 8.41 (d, J=5.2Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 437 (M+1)⁺

Compound 113N-(4-Bromophenyl)-3,5-dibromo-2-[(6,7-dimethoxy-4-quinolyl)oxy]benzamide

4-Chloro-6,7-dimethoxyquinoline (116 mg), 3,5,4′-tribromosalicylanilide(900 mg), and 4-dimethylaminopyridine (244 mg) were suspended ino-dichlorobenzene (1 ml), and the suspension was stirred at 120° C.overnight. The reaction solution was cooled to room temperature, and thesolvent was removed by distillation under the reduced pressure. Waterwas then added to the residue, and the mixture was extracted withchloroform. The chloroform layer was washed with water and was driedover anhydrous sodium sulfate. The solvent was removed therefrom bydistillation under the reduced pressure, and the residue was purified bycolumn chromatography using acetone-hexane to give the title compound(17 mg, yield 6%).

¹H-NMR (CDCl₃, 400 MHz): δ 3.86 (s, 3H), 4.03 (s, 3H), 6.98 (s, 1H),7.06 (m, 4H), 7.48 (m, 3H), 7.60 (d, J=2.4 Hz, 1H), 8.70 (d, J=4.9 Hz,1H)

Mass spectrometric value (ESI−MS, m/z): 636 (M−1)⁻

Compound 114N-(1-Naphthalenyl)-3-[(6,7-dimethoxy-4-quinolyl)oxy]-2-naphthamide

4-Chloro-6,7-dimethoxyquinoline (111 mg), naphthol AS-BO (626 mg), and4-dimethylaminopyridine (244 mg) were suspended in monochlorobenzene (2ml), and the suspension was stirred at 130° C. overnight. The reactionsolution was cooled to room temperature, water was then added to thereaction solution, and the mixture was extracted with ethyl acetate. Theethyl acetate layer was then washed with water and saturated brine andwas dried over anhydrous sodium sulfate. The solvent was removedtherefrom by distillation under the reduced pressure, and the residuewas purified by chromatography on silica gel using ethyl acetate-hexanefor development to give the title compound (43 mg, yield 17%).

Mass spectrometric value (ESI−MS, m/z): 501 (M+1)⁺

Compound 115 4-[(6-Methyl-3-pyridyl)oxy]-6,7-dimethoxyquinoline

4-Chloro-6,7-dimethoxyquinoline (229 mg),3-hydroxy-2-iodo-6-methylpyridine (486 mg), and 4-dimethylaminopyridine(390 mg) were suspended in o-dichlorobenzene (5 ml), and the suspensionwas stirred at 140° C. overnight. The reaction solution was cooled toroom temperature and was then purified by column chromatography usingacetone-chloroform to give the title compound (186 mg, yield 61%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.63 (s, 3H), 4.06 (s, 3H), 4.06 (s, 3H),6.44 (d, J=5.4 Hz, 1H), 7.26 (d, J=8.3 Hz, 1H), 7.42 (dd, J=2.7 Hz, 8.6Hz, 1H), 7.44 (s, 1H), 7.54 (s, 1H), 8.46 (d, J=2.7 Hz, 1H), 8.51 (d,J=5.1 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 297 (M+1)⁺

Compound 116 4-[(2-Iodo-6-methyl-3-pyridyl)oxy]-6,7-dimethoxy-quinoline

4-Chloro-6,7-dimethoxyquinoline (229 mg),3-hydroxy-2-iodo-6-methylpyridine (486 mg), and 4-dimethylaminopyridine(390 mg) were suspended in o-dichlorobenzene (5 ml), and the suspensionwas stirred at 140° C. overnight. The reaction solution was cooled toroom temperature and was then purified by column chromatography usingacetone-chloroform to give the title compound (47 mg, yield 11%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.62 (s, 3H), 4.06 (s, 3H), 4.07 (s, 3H),6.35 (d, J=5.4 Hz, 1H), 7.19 (d, J=8.1 Hz, 1H), 7.31 (d, J=8.1 Hz, 1H),7.46 (s, 1H), 7.58 (s, 1H), 8.51 (d, J=5.4 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 423 (M+1)⁺

Compound 1171-{[3-(6,7-Dimethoxy-4-quinolyl)oxy]-6-methyl-2-pyridyl}-1-ethanone

2,6-Lutidine-α²,3-diol (0.75 g) was dissolved in methanol/methylenechloride (5 ml/15 ml) to prepare a solution. Manganese dioxide (2.78 g)was added to the solution, and the mixture was stirred at roomtemperature overnight. The reaction solution was filtered throughCelite, and the solvent was removed therefrom by distillation under thereduced pressure. The residue was purified by column chromatographyusing acetone-chloroform to give3-hydroxy-6-methyl-2-pyridinecarbaldehyde (642 mg, yield 87%).

4-Chloro-6,7-dimethoxyquinoline (330 mg),3-hydroxy-6-methyl-2-pyridinecarbaldehyde (200 mg), and4-dimethylaminopyridine (360 mg) were suspended in o-dichlorobenzene (7ml), and the suspension was stirred at 150° C. for 3 hr. The reactionsolution was cooled to room temperature and was then purified by columnchromatography using acetone-chloroform to give3-[6,7-dimethoxy-4-quinolyl]oxy}-6-methyl-2-pyridinecarbaldehyde (24 mg,yield 5%).

3-[6,7-Dimethoxy-4-quinolyl]oxy}-6-methyl-2-pyridine-carbaldehyde (24mg) was dissolved in tetrahydrofuran (4 ml) to prepare a solution whichwas then cooled to 0° C. A 0.94 M methylmagnesiumbromide/tetrahydrofuran solution (0.5 ml) was added to the cooledsolution, and the mixture was stirred at room temperature for one hr.Water was added to the reaction solution, and the mixture was extractedwith ethyl acetate. The ethyl acetate layer was then washed with waterand saturated brine and was dried over anhydrous sodium sulfate. Thesolvent was removed therefrom by distillation under the reducedpressure, and the residue was used in the next reaction withoutpurification.

The residue was dissolved in methylene chloride (4 ml) to prepare asolution. Manganese dioxide (0.7 g) was added to the solution, and themixture was stirred at room temperature overnight. The reaction solutionwas filtered through Celite, and the solvent was removed therefrom bydistillation under the reduced pressure. The residue was purified bycolumn chromatography using acetone-chloroform to give the titlecompound (7 mg, yield 29%) (2 steps).

¹H-NMR (CDCl₃, 400 MHz): δ 2.63 (s, 3H), 2.67 (s, 3H), 4.05 (s, 3H),4.05 (s, 3H), 6.28 (d, J=5.1 Hz, 1H), 7.40 (d, J=8.6 Hz, 1H), 7.44 (s,1H), 7.46 (d, J=8.3 Hz, 1H), 7.57 (s, 1H), 8.47 (d, J=5.2 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 339 (M+1)⁺

Compound 118 4-(2-Acetyl-4-methoxyphenoxy)-6-methoxy-7-quinolyl4-morpholine carboxylate

1-{2-[(7-Hydroxy-6-methoxy-4-quinolyl)oxy]-5-methoxyphenyl}-1-ethanone(intermediate 4) (86 mg), morpholine-4-carbonyl chloride (114 mg), andpotassium carbonate (175 mg) were suspended in N,N-dimethylformamide (2ml), and the suspension was stirred at room temperature overnight. Waterwas added to the reaction solution, and the mixture was extracted withethyl acetate. The ethyl acetate layer was then washed with water andsaturated brine and was dried over anhydrous sodium sulfate. The solventwas removed therefrom by distillation under the reduced pressure, andthe residue was purified by thin layer chromatography usingmethanol-chloroform to give the title compound (17 mg, yield 15%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.42 (s, 3H), 3.29 (m, 4H), 3.60 (m, 4H),3.82 (s, 3H), 3.95 (s, 3H), 6.32 (d, J=5.2 Hz, 1H), 7.02-7.09 (m, 2H),7.36 (d, J=2.8 Hz, 1H), 7.54 (s, 1H), 7.87 (s, 1H), 8.43 (d, J=5.2 Hz,1H)

Mass spectrometric value (ESI−MS, m/z): 453 (M+1)⁺

Compound 1191-(2-{[7-(2-Chloroethoxy)-6-methoxy-4-quinolyl]oxy}-5-methoxyphenyl)-1-ethanone

1-{2-[(7-Hydroxy-6-methoxy-4-quinolyl)oxy]-5-methoxyphenyl}-1-ethanone(100 mg), 1-bromo-2-chloroethane (127 mg), and potassium carbonate (204mg) were suspended in N,N-dimethylformamide (3 ml), and the mixture wasstirred at room temperature overnight. Water was added to the reactionsolution, and the mixture was extracted with ethyl acetate. The ethylacetate layer was then washed with water and saturated brine and wasdried over anhydrous sodium sulfate. The solvent was removed therefromby distillation under the reduced pressure, and the residue was purifiedby thin layer chromatography using acetone-hexane to give the titlecompound (107 mg, yield 30%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.41 (s, 3H), 3.82 (s, 3H), 3.88 (t, J=6.4Hz, 2H), 3.97 (s, 3H), 4.39 (t, J=6.4 Hz, 2H), 6.31 (d, J=5.4 Hz, 1H),7.02-7.08 (m, 2H), 7.28-7.38 (m, 2H), 7.52 (s, 1H), 8.42 (d, J=5.4 Hz,1H)

Mass spectrometric value (ESI−MS, m/z): 402 (M+1)⁺

Compound 1201-(5-Methoxy-2-{[6-methoxy-7-(2-morpholinoethoxy)-4-quinolyl]oxy}phenyl)-1-ethanone

1-(2-{[7-(2-Chloroethoxy)-6-methoxy-4-quinolyl]oxy}-5-methoxyphenyl)-1-ethanone(compound 119) (89 mg), morpholine (57 mg), and potassium carbonate (152mg) were suspended in N,N-dimethylformamide (2 ml), and the suspensionwas stirred at 80° C. overnight. The reaction solution was cooled toroom temperature, water was then added to the reaction solution, and themixture was extracted with ethyl acetate. The ethyl acetate layer wasthen washed with water and saturated brine and was dried over anhydroussodium sulfate. The solvent was removed therefrom by distillation underthe reduced pressure, and the residue was purified by thin layerchromatography using methanol-chloroform to give the title compound (24mg, yield 24%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.42 (s, 3H), 2.58 (m, 4H), 2.89 (t, J=5.8Hz, 2H), 3.68 (m, 4H), 3.81 (s, 3H), 3.95 (s, 3H), 4.28 (t, J=5.8 Hz,2H), 6.30 (d, J=5.2 Hz, 1H), 7.01-7.08 (m, 2H), 7.35 (d, J=2.8 Hz, 1H),7.37 (s, 1H), 7.49 (s, 1H), 8.41 (d, J=5.2 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 453 (M+1)⁺

Compound 1211-(2-{[7-(3-Chloropropoxy)-6-methoxy-4-quinolyl]oxy}-5-methoxyphenyl)-1-ethanone

1-{2-[(7-Hydroxy-6-methoxy-4-quinolyl)oxy]-5-methoxyphenyl}-1-ethanone(100 mg), 1-bromo-3-chloropropane (138 mg), and potassium carbonate (204mg) were suspended in N,N-dimethylformamide (3 ml), and the suspensionwas stirred at room temperature overnight. Water was added to thereaction solution, and the mixture was extracted with ethyl acetate. Theethyl acetate layer was then washed with water and saturated brine andwas dried over anhydrous sodium sulfate. The solvent was removedtherefrom by distillation under the reduced pressure, and the residuewas purified by thin layer chromatography using acetone-hexane to givethe title compound (123 mg, yield 34%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.32 (m, 2H), 2.41 (s, 3H), 3.72 (t, J=6.4Hz, 2H), 3.81 (s, 3H), 3.97 (s, 3H), 4.28 (t, J=6.4 Hz, 2H), 6.31 (d,J=5.3 Hz, 1H), 7.01-7.08 (m, 2H), 7.29 (d, J=2.8 Hz, 1H), 7.35 (s, 1H),7.49 (s, 1H), 8.41 (d, J=5.3 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 416 (M+1)⁺

Compound 1221-(5-Methoxy-2-{[6-methoxy-7-(3-morpholinopropoxy)-4-quinolyl]oxy}phenyl)-1-ethanone

1-(2-{[7-(3-Chloropropoxy)-6-methoxy-4-quinolyl]oxy}-5-methoxyphenyl)-1-ethanone(compound 121) (100 mg), morpholine (63 mg), and potassium carbonate(166 mg) were suspended in N,N-dimethylformamide (2 ml), and thesuspension was stirred at 80° C. overnight. The reaction solution wascooled to room temperature, water was then added to the reactionsolution, and the mixture was extracted with ethyl acetate. The ethylacetate layer was then washed with water and saturated brine and wasdried over anhydrous sodium sulfate. The solvent was removed therefromby distillation under the reduced pressure, and the residue was purifiedby thin layer chromatography using methanol-chloroform to give the titlecompound (55 mg, yield 49%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.06 (m, 2H), 2.41 (m, 7H), 2.51 (t, J=6.8Hz, 2H), 3.65 (m, 4H), 3.80 (s, 3H), 3.95 (s, 3H), 4.20 (t, J=6.8 Hz,2H), 6.30 (d, J=5.2 Hz, 1H), 7.01-7.08 (m, 2H), 7.34 (d, J=2.8 Hz, 1H),7.37 (s, 1H), 7.45 (s, 1H), 8.40 (d, J=5.2 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 467 (M+1)⁺

Compound 123(2-{[7-(2-Chloroethoxy)-6-methoxy-4-quinolyl]oxy}-5-methylphenyl)(phenyl)methanone

{2-[(7-Hydroxy-6-methoxy-4-quinolyl)oxy]-5-methylphenyl}-(phenyl)methanone(500 mg), 1-bromo-2-chloroethane (245 mg), and potassium carbonate (897mg) were suspended in N,N-dimethylformamide (20 ml), and the suspensionwas stirred at room temperature overnight. Water was added to thereaction solution, and the mixture was extracted with ethyl acetate. Theethyl acetate layer was then washed with water and saturated brine andwas dried over anhydrous sodium sulfate. The solvent was removedtherefrom by distillation under the reduced pressure, and the residuewas purified by thin layer chromatography using acetone-hexane to givethe title compound (465 mg, yield 80%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.41 (s, 3H), 3.75 (s, 3H), 3.85 (t, J=6.0Hz, 2H), 4.34 (t, J=6.0 Hz, 2H), 6.38 (d, J=5.2 Hz, 1H), 6.88 (s, 1H),7.10 (d, J=7.2 Hz, 1H), 7.25 (m, 3H), 7.41 (m, 3H), 7.61 (m, 2H), 8.34(d, J=5.2 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 448 (M+1)⁺

Compound 124{2-[(7-{2-[(2-Hydroxyethyl)amino]ethoxy}-6-methoxy-4-quinolyl)oxy]-5-methylphenyl}(phenyl)methanone

(2-{[7-(2-Chloroethoxy)-6-methoxy-4-quinolyl]oxy}-5-methylphenyl)(phenyl)methanone(compound 123) (50 mg), 2-aminoethanol (20 mg), and potassium carbonate(76 mg) were suspended in N,N-dimethylformamide (3 ml), and thesuspension was stirred at 80° C. overnight. The reaction solution wascooled to room temperature, water was then added to the reactionsolution, and the mixture was extracted with ethyl acetate. The ethylacetate layer was then washed with water and saturated brine and wasdried over anhydrous sodium sulfate. The solvent was removed therefromby distillation under the reduced pressure, and the residue was purifiedby thin layer chromatography using methanol-chloroform to give the titlecompound (23 mg, yield 44%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.39 (s, 3H), 2.81 (m, 2H), 3.08 (m, 2H),3.62 (m, 2H), 3.70 (s, 3H), 4.18 (m, 2H), 6.31 (d, J=5.4 Hz, 1H), 6.80(s, 1H), 7.07 (d, J=7.2 Hz, 1H), 7.22-7.26 (m, 3H), 7.34-7.39 (m, 3H),7.62 (m, 2H), 8.32 (d, J=5.4 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 495 (M+Na)⁺

Compound 125[2-({7-[2-(Diethylamino)ethoxy]-6-methoxy-4-quinolyl}oxy)-5-methylphenyl](phenyl)methanone

(2-{[7-(2-Chloroethoxy)-6-methoxy-4-quinolyl]oxy}-5-methylphenyl)(phenyl)methanone(50 mg), diethylamine (24 mg), and potassium carbonate (76 mg) weresuspended in N,N-dimethylformamide (3 ml), and the suspension wasstirred at 80° C. overnight. The reaction solution was cooled to roomtemperature, water was then added to the cooled reaction solution, andthe mixture was extracted with ethyl acetate. The ethyl acetate layerwas then washed with water and saturated brine and was dried overanhydrous sodium sulfate. The solvent was removed therefrom bydistillation under the reduced pressure, and the residue was purified bythin layer chromatography using methanol-chloroform to give the titlecompound (7 mg, yield 13%).

¹H-NMR (CDCl₃, 400 MHz): δ 1.11-1.20 (m, 6H), 2.40 (s, 3H), 2.60-3.13(m, 6H), 3.71 (s, 3H), 4.24 (m, 2H), 6.32 (d, J=5.4 Hz, 1H), 6.80 (s,1H), 7.08 (d, J=7.2 Hz, 1H), 7.22-7.26 (m, 3H), 7.34-7.39 (m, 3H), 7.61(m, 2H), 8.34 (d, J=5.4 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 485 (M+1)⁺

Compound 126{2-[(7-{2-[4-(Hydroxymethyl)piperidino]ethoxy}-6-methoxy-4-quinolyl)oxy]-5-methylphenyl}(phenyl)methanone

(2-{[7-(2-Chloroethoxy)-6-methoxy-4-quinolyl]oxy}-5-methylphenyl)(phenyl)methanone(50 mg), 4-piperidine methanol (38 mg), and potassium carbonate (76 mg)were suspended in N,N-dimethylformamide (3 ml), and the suspension wasstirred at 80° C. overnight. The reaction solution was cooled to roomtemperature, water was then added to the reaction solution, and themixture was extracted with ethyl acetate. The ethyl acetate layer wasthen washed with water and saturated brine and was dried over anhydroussodium sulfate. The solvent was removed therefrom by distillation underthe reduced pressure, and the residue was purified by thin layerchromatography using methanol-chloroform to give the title compound (31mg, yield 54%).

¹H-NMR (CDCl₃, 400 MHz): δ 1.18-1.35 (m, 2H), 1.41-1.51 (m, 1H), 1.68(m, 2H), 2.11 (m, 2H), 2.39 (s, 3H), 2.86 (t, J=6.4 Hz, 2H), 2.99 (m,2H), 3.43 (d, J=6.2 Hz, 2H), 3.71 (s, 3H), 4.21 (t, J=6.2 Hz, 2H), 6.31(d, J=5.2 Hz, 1H), 6.80 (s, 1H), 7.07 (d, J=7.2 Hz, 1H), 7.22-7.26 (m,3H), 7.34-7.39 (m, 3H), 7.62 (m, 2H), 8.32 (d, J=5.2 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 549 (M+Na)⁺

Compound 127[5-Methyl-2-({6-methoxy-7-[2-(4-tetrahydro-1-pyrrolylpiperidino)ethoxy]-4-quinolyl}oxy)phenyl](phenyl)methanone

(2-{[7-(2-Chloroethoxy)-6-methoxy-4-quinolyl]oxy}-5-methylphenyl)(phenyl)methanone(96 mg), 4-(1-pyrrolidinyl)piperidine (97 mg), and potassium carbonate(145 mg) were suspended in N,N-dimethylformamide (3 ml), and thesuspension was stirred at 80° C. overnight. The reaction solution wascooled to room temperature, water was then added to the reactionsolution, and the mixture was extracted with ethyl acetate. The ethylacetate layer was then washed with water and saturated brine and wasdried over anhydrous sodium sulfate. The solvent was removed therefromby distillation under the reduced pressure, and the residue was purifiedby thin layer chromatography using methanol-chloroform to give the titlecompound (43 mg, yield 41%).

¹H-NMR (CDCl₃, 400 MHz): δ 1.47-1.57 (m, 2H), 1.69-1.82 (m, 6H), 1.98(m, 1H), 2.10 (m, 2H), 2.38 (s, 3H), 2.51 (m, 4H), 2.82 (t, J=6.4 Hz,2H), 2.96 (m, 2H), 3.70 (s, 3H), 4.18 (t, J=6.4 Hz, 2H), 6.30 (d, J=5.4Hz, 1H), 6.79 (s, 1H), 7.07 (d, J=7.2 Hz, 1H), 7.20-7.25 (m, 3H),7.34-7.38 (m, 3H), 7.60 (m, 2H), 8.32 (d, J=5.4 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 566 (M+1)⁺

Compound 128[2-({6-Methoxy-7-[2-(1-piperazino)ethoxy]-4-quinolyl}oxy)-5-methylphenyl](phenyl)methanone

(2-{[7-(2-Chloroethoxy)-6-methoxy-4-quinolyl]oxy}-5-methylphenyl)(phenyl)methanone(50 mg), piperazine (28 mg), and potassium carbonate (76 mg) weresuspended in N,N-dimethylformamide (3 ml), and the suspension wasstirred at 80° C. overnight. The reaction solution was cooled to roomtemperature, water was then added to the reaction solution, and themixture was extracted with ethyl acetate. The ethyl acetate layer wasthen washed with water and saturated brine and was dried over anhydroussodium sulfate. The solvent was removed therefrom by distillation underthe reduced pressure, and the residue was purified by thin layerchromatography using methanol-chloroform to give the title compound (91mg, yield 93%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.39 (s, 3H), 2.51 (m, 4H), 2.84 (m, 6H),3.71 (s, 3H), 4.18 (t, J=6.1 Hz, 2H), 6.31 (d, J=5.3 Hz, 1H), 6.80 (s,1H), 7.07 (d, J=7.2 Hz, 1H), 7.22-7.26 (m, 3H), 7.34-7.39 (m, 3H), 7.62(m, 2H), 8.32 (d, J=5.3 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 520 (M+Na)⁺

Compound 129[2-({6-Methoxy-7-[2-(4-methylpiperazino)ethoxy]-4-quinolyl}oxy)-5-methylphenyl](phenyl)methanone

(2-{[7-(2-Chloroethoxy)-6-methoxy-4-quinolyl]oxy}-5-methylphenyl)(phenyl)methanone(50 mg), 4-methylpiperazine (33 mg), and potassium carbonate (76 mg)were suspended in N,N-dimethylformamide (3 ml), and the suspension wasstirred at 80° C. overnight. The reaction solution was cooled to roomtemperature, water was then added to the reaction solution, and themixture was extracted with ethyl acetate. The ethyl acetate layer wasthen washed with water and saturated brine and was dried over anhydroussodium sulfate. The solvent was removed therefrom by distillation underthe reduced pressure, and the residue was purified by thin layerchromatography using methanol-chloroform to give the title compound (29mg, yield 52%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.24 (s, 3H), 2.39-2.44 (m, 7H), 2.59 (m,4H), 2.85 (t, J=6.1 Hz, 2H), 3.70 (s, 3H), 4.20 (t, J=6.1 Hz, 2H), 6.31(d, J=5.2 Hz, 1H), 6.80 (s, 1H), 7.07 (d, J=7.3 Hz, 1H), 7.22-7.26 (m,3H), 7.34-7.39 (m, 3H), 7.62 (m, 2H), 8.33 (d, J=5.2 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 534 (M+Na)⁺

Compound 130(5-Methyl-2-{[6-methoxy-7-(2-morpholinoethoxy)-4-quinolyl]oxy}phenyl)(phenyl)methanone

(2-{[7-(2-Chloroethoxy)-6-methoxy-4-quinolyl]oxy}-5-methylphenyl)(phenyl)methanone(50 mg), morpholine (29 mg), and potassium carbonate (76 mg) weresuspended in N,N-dimethylformamide (3 ml), and the suspension wasstirred at 80° C. overnight. The reaction solution was cooled to roomtemperature, water was then added to the reaction solution, and themixture was extracted with ethyl acetate. The ethyl acetate layer wasthen washed with water and saturated brine and was dried over anhydroussodium sulfate. The solvent was removed therefrom by distillation underthe reduced pressure, and the residue was purified by thin layerchromatography using methanol-chloroform to give the title compound (35mg, yield 64%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.39 (s, 3H), 2.54 (m, 4H), 2.84 (t, J=6.1Hz, 2H), 3.65-3.71 (m, 7H), 4.16 (t, J=6.1 Hz, 2H), 6.32 (d, J=5.3 Hz,1H), 6.81 (s, 1H), 7.07 (d, J=7.2 Hz, 1H), 7.22-7.26 (m, 3H), 7.34-7.39(m, 3H), 7.62 (m, 2H), 8.33 (d, J=5.3 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 521 (M+Na)⁺

Compound 131[2-({7-[2-(1-Imidazoyl)ethoxy]-6-methoxy-4-quinolyl}-oxy)-5-methylphenyl](phenyl)methanone

(2-{[7-(2-Chloroethoxy)-6-methoxy-4-quinolyl]oxy}-5-methylphenyl)(phenyl)methanone(50 mg), imidazole (22 mg), and potassium carbonate (76 mg) weresuspended in N,N-dimethylformamide (3 ml), and the suspension wasstirred at 80° C. overnight. The reaction solution was cooled to roomtemperature, water was then added to the reaction solution, and themixture was extracted with ethyl acetate. The ethyl acetate layer wasthen washed with water and saturated brine and was dried over anhydroussodium sulfate. The solvent was removed therefrom by distillation underthe reduced pressure, and the residue was purified by thin layerchromatography using methanol-chloroform to give the title compound (33mg, yield 63%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.39 (s, 3H), 3.71 (s, 3H), 4.25 (m, 2H),4.33 (m, 2H), 6.32 (d, J=5.2 Hz, 1H), 6.82 (s, 1H), 6.98-7.40 (m, 9H),7.60 (m, 3H), 8.32 (d, J=5.2 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 502 (M+Na)⁺

Compound 132(2-{[7-(3-Chloropropoxy)-6-methoxy-4-quinolyl]oxy}-5-methylphenyl)(phenyl)methanone

{2-[(7-Hydroxy-6-methoxy-4-quinolyl)oxy]-5-methylphenyl}-(phenyl)methanone(200 mg), 1-bromo-3-chloropropane (245 mg), and potassium carbonate (358mg) were suspended in N,N-dimethylformamide (5 ml), and the suspensionwas stirred at room temperature overnight. Water was added to thereaction solution, and the mixture was extracted with ethyl acetate. Theethyl acetate layer was then washed with water and saturated brine andwas dried over anhydrous sodium sulfate. The solvent was removedtherefrom by distillation under the reduced pressure, and the residuewas purified by thin layer chromatography using acetone-hexane to givethe title compound (210 mg, yield 87%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.25 (m, 2H), 2.38 (s, 3H), 3.69 (m, 5H),4.18 (t, J=6.2 Hz, 2H), 6.30 (d, J=5.3 Hz, 1H), 6.80 (s, 1H), 7.02 (d,J=7.2 Hz, 1H), 7.23-7.26 (m, 3H), 7.31-7.37 (m, 3H), 7.59 (m, 2H), 8.31(d, J=5.3 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 462 (M+1)⁺

Compound 133{2-[(7-{3-[(2-Hydroxyethyl)amino]propoxy}-6-methoxy-4-quinolyl)oxy]-5-methylphenyl}(phenyl)methanone

(2-{[7-(3-Chloropropoxy)-6-methoxy-4-quinolyl]oxy}-5-methylphenyl)(phenyl)methanone(compound 132) (68 mg), 4-aminoethanol (25 mg), and potassium carbonate(95 mg) were suspended in N,N-dimethylformamide (3 ml), and thesuspension was stirred at 80° C. overnight. The reaction solution wascooled to room temperature, water was then added to the reactionsolution, and the mixture was extracted with ethyl acetate. The ethylacetate layer was then washed with water and saturated brine and wasdried over anhydrous sodium sulfate. The solvent was removed therefromby distillation under the reduced pressure, and the residue was purifiedby thin layer chromatography using methanol-chloroform to give the titlecompound (36 mg, yield 54%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.01 (m, 2H), 2.39 (s, 3H), 2.72-2.80 (m,4H), 3.60 (m, 2H), 3.71 (s, 3H), 4.17 (t, J=6.1 Hz, 2H), 6.31 (d, J=5.2Hz, 1H), 6.80 (s, 1H), 7.07 (d, J=7.2 Hz, 1H), 7.22-7.26 (m, 3H),7.34-7.39 (m, 3H), 7.62 (m, 2H), 8.32 (d, J=5.2 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 509 (M+Na)⁺

Compound 134[2-({7-[3-(Diethylamino)propoxy]-6-methoxy-4-quinolyl}oxy)-5-methylphenyl](phenyl)methanone

(2-{[7-(3-Chloropropoxy)-6-methoxy-4-quinolyl]oxy}-5-methylphenyl)(phenyl)methanone(68 mg), diethylamine (30 mg), and potassium carbonate (95 mg) weresuspended in N,N-dimethylformamide (3 ml), and the suspension wasstirred at 80° C. overnight. The reaction solution was cooled to roomtemperature, water was then added to the reaction solution, and themixture was extracted with ethyl acetate. The ethyl acetate layer wasthen washed with water and saturated brine and was dried over anhydroussodium sulfate. The solvent was removed therefrom by distillation underthe reduced pressure, and the residue was purified by thin layerchromatography using methanol-chloroform to give the title compound (26mg, yield 38%).

¹H-NMR (CDCl₃, 400 MHz): δ 0.97 (t, J=7.2 Hz, 6H), 1.99 (m, 2H), 2.39(s, 3H), 2.49 (m, 4H), 2.56 (t, J=7.6 Hz, 2H), 3.71 (s, 3H), 4.11 (t,J=6.8 Hz, 2H), 6.30 (d, J=5.4 Hz, 1H), 6.79 (s, 1H), 7.07 (d, J=7.2 Hz,1H), 7.19-7.24 (m, 3H), 7.33-7.39 (m, 3H), 7.62 (m, 2H), 8.32 (d, J=5.4Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 499 (M+1)⁺

Compound 135{2-[(7-{3-[4-(Hydroxymethyl)piperidino]propoxy}-6-methoxy-4-quinolyl)oxy]-5-methylphenyl}(phenyl)methanone

(2-{[7-(3-Chloropropoxy)-6-methoxy-4-quinolyl]oxy}-5-methylphenyl)(phenyl)methanone(62 mg), 4-piperidine ethanol (25 mg), and potassium carbonate (100 mg)were suspended in N,N-dimethylformamide (4 ml), and the suspension wasstirred at 80° C. overnight. The reaction solution was cooled to roomtemperature, water was then added to the reaction solution, and themixture was extracted with ethyl acetate. The ethyl acetate layer wasthen washed with water and saturated brine and was dried over anhydroussodium sulfate. The solvent was removed therefrom by distillation underthe reduced pressure, and the residue was purified by thin layerchromatography using methanol-chloroform to give the title compound (55mg, yield 75%).

¹H-NMR (CDCl₃, 400 MHz): δ 1.48 (m, 2H), 1.76 (m, 2H), 1.73 (m, 2H),2.16-2.29 (m, 4H), 2.39 (s, 3H), 2.79 (m, 2H), 3.22 (m, 2H), 3.44 (m,2H), 3.70 (s, 3H), 4.06 (m, 1H), 6.32 (d, J=5.4 Hz, 1H), 6.81 (s, 1H),7.07 (d, J=7.2 Hz, 1H), 7.20-7.26 (m, 3H), 7.34-7.40 (m, 3H), 7.62 (m,2H), 8.32 (d, J=5.4 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 541 (M+1)⁺

Compound 136[5-Methyl-2-({6-methoxy-7-[3-(4-tetrahydro-1-pyrrolylpiperidino)propoxy]-4-quinolyl}oxy)phenyl](phenyl)methanone

(2-{[7-(3-Chloropropoxy)-6-methoxy-4-quinolyl]oxy}-5-methylphenyl)(phenyl)methanone(112 mg), 4-(1-pyrrolidinyl)piperidine (111 mg), and potassium carbonate(166 mg) were suspended in N,N-dimethylformamide (3 ml), and thesuspension was stirred at 80° C. overnight. The reaction solution wascooled to room temperature, water was then added to the reactionsolution, and the mixture was extracted with ethyl acetate. The ethylacetate layer was then washed with water and saturated brine and wasdried over anhydrous sodium sulfate. The solvent was removed therefromby distillation under the reduced pressure, and the residue was purifiedby thin layer chromatography using methanol-chloroform to give the titlecompound (47 mg, yield 35%).

¹H-NMR (CDCl₃, 400 MHz): δ 1.44-1.54 (m, 2H), 1.69-2.22 (m, 11H),2.38-2.50 (m, 9H), 2.85 (m, 2H), 3.70 (s, 3H), 4.10 (t, J=6.8 Hz, 2H),6.30 (d, J=5.4 Hz, 1H), 6.79 (s, 1H), 7.07 (d, J=7.2 Hz, 1H), 7.20-7.25(m, 3H), 7.34-7.38 (m, 3H), 7.61 (m, 2H), 8.31 (d, J=5.4 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 580 (M+1)⁺

Compound 137[2-({6-Methoxy-7-[3-(1-piperazino)propoxy]-4-quinolyl}oxy)-5-methylphenyl](phenyl)methanone

(2-{[7-(3-Chloropropoxy)-6-methoxy-4-quinolyl]oxy}-5-methylphenyl)(phenyl)methanone(68 mg), piperazine (36 mg), and potassium carbonate (95 mg) weresuspended in N,N-dimethylformamide (3 ml), and the suspension wasstirred at 80° C. overnight. The reaction solution was cooled to roomtemperature, water was then added to the cooled reaction solution, andthe mixture was extracted with ethyl acetate. The ethyl acetate layerwas then washed with water and saturated brine and was dried overanhydrous sodium sulfate. The solvent was removed therefrom bydistillation under the reduced pressure, and the residue was purified bythin layer chromatography using methanol-chloroform to give the titlecompound (43 mg, yield 61%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.01 (m, 2H), 2.39-2.47 (m, 9H), 2.82 (m,4H), 3.73 (s, 3H), 4.12 (t, J=6.4 Hz, 2H), 6.31 (d, J=5.2 Hz, 1H), 6.80(s, 1H), 7.07 (d, J=7.2 Hz, 1H), 7.22-7.26 (m, 3H), 7.34-7.39 (m, 3H),7.62 (m, 2H), 8.32 (d, J=5.2 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 512 (M+1)⁺

Compound 138[2-({6-Methoxy-7-[3-(4-methylpiperazino)propoxy]-4-quinolyl}oxy)-5-methylphenyl](phenyl)methanone

(2-{[7-(3-Chloropropoxy)-6-methoxy-4-quinolyl]oxy}-5-methylphenyl)(phenyl)methanone(68 mg), 4-methylpiperazine (42 mg), and potassium carbonate (95 mg)were suspended in N,N-dimethylformamide (3 ml), and the suspension wasstirred at 80° C. overnight. The reaction solution was cooled to roomtemperature, water was then added to the reaction solution, and themixture was extracted with ethyl acetate. The ethyl acetate layer wasthen washed with water and saturated brine and was dried over anhydroussodium sulfate. The solvent was removed therefrom by distillation underthe reduced pressure, and the residue was purified by thin layerchromatography using methanol-chloroform to give the title compound (54mg, yield 75%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.01 (m, 2H), 2.21 (s, 3H), 2.38-2.49 (m,13H), 3.70 (s, 3H), 4.11 (t, J=6.4 Hz, 2H), 6.30 (d, J=5.2 Hz, 1H), 6.79(s, 1H), 7.07 (d, J=7.2 Hz, 1H), 7.20-7.25 (m, 3H), 7.33-7.42 (m, 3H),7.61 (m, 2H), 8.32 (d, J=5.2 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 526 (M+1)⁺

Compound 139(5-Methyl-2-{[6-methoxy-7-(3-morpholinopropoxy)-4-quinolyl]oxy}phenyl)(phenyl)methanone

(2-{[7-(3-Chloropropoxy)-6-methoxy-4-quinolyl]oxy}-5-methylphenyl)(phenyl)methanone(62 mg), morpholine (40 mg), and potassium carbonate (100 mg) weresuspended in N,N-dimethylformamide (4 ml), and the suspension wasstirred at 80° C. overnight. The reaction solution was cooled to roomtemperature, water was then added to the reaction solution, and themixture was extracted with ethyl acetate. The ethyl acetate layer wasthen washed with water and saturated brine and was dried over anhydroussodium sulfate. The solvent was removed therefrom by distillation underthe reduced pressure, and the residue was purified by thin layerchromatography using methanol-chloroform to give the title compound (45mg, yield 66%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.02 (m, 2H), 2.39-2.54 (m, 9H), 3.63-3.71(m, 7H), 4.04 (m, 2H), 6.31 (d, J=5.3 Hz, 1H), 6.81 (s, 1H), 7.07 (d,J=7.2 Hz, 1H), 7.19-7.25 (m, 3H), 7.33-7.39 (m, 3H), 7.62 (m, 2H), 8.32(d, J=5.3 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 513 (M+1)⁺

Compound 140[2-({7-[3-(1-Imidazoyl)propoxy]-6-methoxy-4-quinolyl}oxy)-5-methylphenyl](phenyl)methanone

(2-{[7-(3-Chloropropoxy)-6-methoxy-4-quinolyl]oxy}-5-methylphenyl)(phenyl)methanone(68 mg), imidazole (28 mg), and potassium carbonate (95 mg) weresuspended in N,N-dimethylformamide (3 ml), and the suspension wasstirred at 80° C. overnight. The reaction solution was cooled to roomtemperature, water was then added to the reaction solution, and themixture was extracted with ethyl acetate. The ethyl acetate layer wasthen washed with water and saturated brine and was dried over anhydroussodium sulfate. The solvent was removed therefrom by distillation underthe reduced pressure, and the residue was purified by thin layerchromatography using methanol-chloroform to give the title compound (59mg, yield 87%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.23 (m, 2H), 2.38 (s, 3H), 3.73 (s, 3H),3.99 (t, J=6.0 Hz, 2H), 4.14 (t, J=6.8 Hz, 2H), 6.32 (d, J=5.2 Hz, 1H),6.84 (m, 2H), 6.96 (s, 1H), 7.07 (d, J=7.2 Hz, 1H), 7.17-7.26 (m, 3H),7.33-7.41 (m, 4H), 7.61 (m, 2H), 8.32 (d, J=5.2 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 516 (M+Na)⁺

Compound 141(2-{[7-(4-Chlorobutoxy)-6-methoxy-4-quinolyl]oxy}-5-methylphenyl)(phenyl)methanone

{2-[(7-Hydroxy-6-methoxy-4-quinolyl)oxy]-5-methylphenyl}-(phenyl)methanone(500 mg), 1-bromo-3-chlorobutane (668 mg), and potassium carbonate (896mg) were suspended in N,N-dimethylformamide (20 ml), and the suspensionwas stirred at room temperature overnight. Water was added to thereaction solution, and the mixture was extracted with ethyl acetate. Theethyl acetate layer was then washed with water and saturated brine andwas dried over anhydrous sodium sulfate. The solvent was removedtherefrom by distillation under the reduced pressure, and the residuewas purified by thin layer chromatography using acetone-hexane to givethe title compound (584 mg, yield 95%).

¹H-NMR (CDCl₃, 400 MHz): δ 1.95 (m, 4H), 2.40 (s, 3H), 3.57 (t, J=6.4Hz, 2H), 3.72 (s, 3H), 4.11 (t, J=6.4 Hz, 2H), 6.34 (d, J=5.4 Hz, 1H),6.83 (s, 1H), 7.09 (d, J=7.2 Hz, 1H), 7.22-7.28 (m, 3H), 7.35-7.40 (m,3H), 7.61 (m, 2H), 8.33 (d, J=5.4 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 476 (M+1)⁺

Compound 142{2-[(7-{4-[(2-Hydroxyethyl)amino]butoxy}-6-methoxy-4-quinolyl)oxy]-5-methylphenyl}(phenyl)methanone

(2-{[7-(4-Chlorobutoxy)-6-methoxy-4-quinolyl]oxy}-5-methylphenyl)(phenyl)methanone(compound 142) (60 mg), 4-aminoethanol (24 mg), and potassium carbonate(90 mg) were suspended in N,N-dimethylformamide (2 ml), and thesuspension was stirred at 80° C. overnight. The reaction solution wascooled to room temperature, water was then added to the reactionsolution, and the mixture was extracted with ethyl acetate. The ethylacetate layer was then washed with water and saturated brine and wasdried over anhydrous sodium sulfate, and the solvent was removedtherefrom by distillation under the reduced pressure. The residue waspurified by thin layer chromatography using methanol-chloroform to givethe title compound (33 mg, yield 51%).

¹H-NMR (CDCl₃, 400 MHz): δ 1.62 (m, 2H), 1.88 (m, 2H), 2.39 (s, 3H),2.65 (t, J=6.8 Hz, 2H), 2.72 (t, J=5.2 Hz, 2H), 3.59 (t, J=5.2 Hz, 2H),3.71 (s, 3H), 4.09 (t, J=6.8 Hz, 2H), 6.30 (d, J=5.4 Hz, 1H), 6.80 (s,1H), 7.07 (d, J=7.2 Hz, 1H), 7.22-7.26 (m, 3H), 7.34-7.39 (m, 3H), 7.61(m, 2H), 8.31 (d, J=5.4 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 501 (M+1)⁺

Compound 143[2-({7-[4-(Diethylamino)butoxy]-6-methoxy-4-quinolyl}oxy)-5-methylphenyl](phenyl)methanone

(2-{[7-(4-Chlorobutoxy)-6-methoxy-4-quinolyl]oxy}-5-methylphenyl)(phenyl)methanone(60 mg), diethylamine (29 mg), and potassium carbonate (90 mg) weresuspended in N,N-dimethylformamide (2 ml), and the suspension wasstirred at 80° C. overnight. The reaction solution was cooled to roomtemperature, water was then added to the reaction solution, and themixture was extracted with ethyl acetate. The ethyl acetate layer wasthen washed with water and saturated brine and was dried over anhydroussodium sulfate. The solvent was removed therefrom by distillation underthe reduced pressure, and the residue was purified by thin layerchromatography using methanol-chloroform to give the title compound (27mg, yield 41%).

¹H-NMR (CDCl₃, 400 MHz): δ 0.96 (t, J=7.2 Hz, 6H), 1.59 (m, 2H), 1.84(m, 2H), 2.39 (s, 3H), 2.48 (m, 4H), 2.56 (t, J=7.6 Hz, 2H), 3.71 (s,3H), 4.07 (t, J=6.8 Hz, 2H), 6.30 (d, J=5.4 Hz, 1H), 6.79 (s, 1H), 7.07(d, J=7.2 Hz, 1H), 7.19-7.24 (m, 3H), 7.33-7.39 (m, 3H), 7.61 (m, 2H),8.32 (d, J=5.2 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 513 (M+1)⁺

Compound 144{2-[(7-{4-[4-(Hydroxymethyl)piperidino]butoxy}-6-methoxy-4-quinolyl)oxy]-5-methylphenyl}(phenyl)methanone

(2-{[7-(4-Chlorobutoxy)-6-methoxy-4-quinolyl]oxy}-5-methylphenyl)(phenyl)methanone(60 mg), 4-piperidine ethanol (45 mg), and potassium carbonate (90 mg)were suspended in N,N-dimethylformamide (2 ml), and the suspension wasstirred at 80° C. overnight. The reaction solution was cooled to roomtemperature, water was then added to the reaction solution, and themixture was extracted with ethyl acetate. The ethyl acetate layer wasthen washed with water and saturated brine and was dried over anhydroussodium sulfate. The solvent was removed therefrom by distillation underthe reduced pressure, and the residue was purified by thin layerchromatography using methanol-chloroform to give the title compound (32mg, yield 41%).

¹H-NMR (CDCl₃, 400 MHz): δ 1.17-1.27 (m, 2H), 1.38-1.46 (m, 1H),1.59-1.66 (m, 4H), 1.80-1.95 (m, 4H), 2.31-2.38 (m, 5H), 2.88 (m, 2H),3.39 (d, J=6.4 Hz, 2H), 3.70 (s, 3H), 4.05 (t, J=6.4 Hz, 2H), 6.31 (d,J=5.2 Hz, 1H), 6.79 (s, 1H), 7.07 (d, J=7.2 Hz, 1H), 7.22-7.26 (m, 3H),7.34-7.39 (m, 3H), 7.60 (m, 2H), 8.31 (d, J=5.2 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 577 (M+Na)⁺

Compound 145[5-Methyl-2-({6-methoxy-7-[4-(4-tetrahydro-1-pyrrolylpiperidino)butoxy]-4-quinolyl}oxy)phenyl](phenyl)methanone

(2-{[7-(4-Chlorobutoxy)-6-methoxy-4-quinolyl]oxy}-5-methylphenyl)(phenyl)methanone(60 mg), 4-(1-pyrrolidinyl)piperidine (60 mg), and potassium carbonate(90 mg) was suspended in N,N-dimethylformamide (3 ml), and thesuspension was stirred at 80° C. overnight. The reaction solution wascooled to room temperature, water was then added to the reactionsolution, and the mixture was extracted with ethyl acetate. The ethylacetate layer was then washed with water and saturated brine and wasdried over anhydrous sodium sulfate. The solvent was removed therefromby distillation under the reduced pressure, and the residue was purifiedby thin layer chromatography using methanol-chloroform to give the titlecompound (69 mg, yield 90%).

¹H-NMR (CDCl₃, 400 MHz): δ 1.44-1.97 (m, 15H), 2.30 (m, 2H), 2.38 (s,3H), 2.50 (m, 4H), 2.85 (m, 2H), 3.70 (s, 3H), 4.07 (t, J=6.8 Hz, 2H),6.30 (d, J=5.4 Hz, 1H), 6.78 (s, 1H), 7.07 (d, J=7.2 Hz, 1H), 7.20-7.25(m, 3H), 7.34-7.38 (m, 3H), 7.61 (m, 2H), 8.32 (d, J=5.4 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 594 (M+1)⁺

Compound 146[5-Methyl-2-({6-methoxy-7-[4-(4-piperidylpiperidino)-butoxy]-4-quinolyl}oxy)phenyl](phenyl)methanone

(2-{[7-(4-Chlorobutoxy)-6-methoxy-4-quinolyl]oxy}-5-methylphenyl)(phenyl)methanone(60 mg), 4-piperidinopiperidine (66 mg), and potassium carbonate (90 mg)were suspended in N,N-dimethylformamide (2 ml), and the suspension wasstirred at 80° C. overnight. The reaction solution was cooled to roomtemperature, water was then added to the reaction solution, and themixture was extracted with ethyl acetate. The ethyl acetate layer wasthen washed with water and saturated brine and was dried over anhydroussodium sulfate. The solvent was removed therefrom by distillation underthe reduced pressure, and the residue was purified by thin layerchromatography using methanol-chloroform to give the title compound (34mg, yield 43%).

¹H-NMR (CDCl₃, 400 MHz): δ 1.34-1.85 (m, 16H), 2.20 (m, 1H), 2.30 (m,2H), 2.38-2.44 (m, 7H), 2.91 (m, 2H), 3.70 (s, 3H), 4.07 (t, J=6.8 Hz,2H), 6.30 (d, J=5.4 Hz, 1H), 6.78 (s, 1H), 7.07 (d, J=7.2 Hz, 1H),7.20-7.25 (m, 3H), 7.34-7.38 (m, 3H), 7.61 (m, 2H), 8.31 (d, J=5.4 Hz,1H)

Mass spectrometric value (ESI−MS, m/z): 608 (M+1)⁺

Compound 147[2-({6-Methoxy-7-[4-(1-piperazino)butoxy]-4-quinolyl}-oxy)-5-methylphenyl](phenyl)methanone

(2-{[7-(4-Chlorobutoxy)-6-methoxy-4-quinolyl]oxy}-5-methylphenyl)(phenyl)methanone(60 mg), piperazine (34 mg), and potassium carbonate (90 mg) weresuspended in N,N-dimethylformamide (2 ml), and the suspension wasstirred at 80° C. overnight. The reaction solution was cooled to roomtemperature, water was then added to the reaction solution, and themixture was extracted with ethyl acetate. The ethyl acetate layer wasthen washed with water and saturated brine and was dried over anhydroussodium sulfate, and the solvent was removed therefrom by distillationunder the reduced pressure. The residue was purified by thin layerchromatography using methanol-chloroform to give the title compound (41mg, yield 60%).

¹H-NMR (CDCl₃, 400 MHz): δ 1.61 (m, 2H), 1.85 (m, 2H), 2.30-2.38 (m, 9H)2.82 (m, 4H), 3.70 (s, 3H), 4.07 (t, J=6.4 Hz, 2H), 6.30 (d, J=5.2 Hz,1H), 6.79 (s, 1H), 7.07 (d, J=7.2 Hz, 1H), 7.22-7.26 (m, 3H), 7.34-7.39(m, 3H), 7.61 (m, 2H), 8.32 (d, J=5.2 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 526 (M+1)⁺

Compound 148[2-({6-Methoxy-7-[4-(4-methylpiperazino)butoxy]-4-quinolyl}oxy)-5-methylphenyl](phenyl)methanone

(2-{[7-(4-Chlorobutoxy)-6-methoxy-4-quinolyl]oxy}-5-methylphenyl)(phenyl)methanone(60 mg), 4-methylpiperazine (39 mg), and potassium carbonate (90 mg)were suspended in N,N-dimethylformamide (2 ml), and the suspension wasstirred at 80° C. overnight. The reaction solution was cooled to roomtemperature, water was then added to the reaction solution, and themixture was extracted with ethyl acetate. The ethyl acetate layer wasthen washed with water and saturated brine and was dried over anhydroussodium sulfate. The solvent was removed therefrom by distillation underthe reduced pressure, and the residue was purified by thin layerchromatography using methanol-chloroform to give the title compound (41mg, yield 60%).

¹H-NMR (CDCl₃, 400 MHz): δ 1.61 (m, 2H), 1.85 (m, 2H), 2.21 (s, 3H),2.29-2.38 (m, 13H), 3.70 (s, 3H), 4.05 (t, J=6.8 Hz, 2H), 6.30 (d, J=5.2Hz, 1H), 6.79 (s, 1H), 7.07 (d, J=7.2 Hz, 1H), 7.20-7.25 (m, 3H),7.33-7.42 (m, 3H), 7.61 (m, 2H), 8.31 (d, J=5.2 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 562 (M+Na)⁺

Compound 149(5-Methyl-2-{[6-methoxy-7-(4-morpholinobutoxy)-4-quinolyl]oxy}phenyl)(phenyl)methanone

(2-{[7-(4-Chlorobutoxy)-6-methoxy-4-quinolyl]oxy}-5-methylphenyl)(phenyl)methanone(60 mg), morpholine (34 mg), and potassium carbonate (90 mg) weresuspended in N,N-dimethylformamide (2 ml), and the suspension wasstirred at 80° C. overnight. The reaction solution was cooled to roomtemperature, water was then added to the reaction solution, and themixture was extracted with ethyl acetate. The ethyl acetate layer wasthen washed with water and saturated brine and was dried over anhydroussodium sulfate. The solvent was removed therefrom by distillation underthe reduced pressure, and the residue was purified by thin layerchromatography using methanol-chloroform to give the title compound (36mg, yield 55%).

¹H-NMR (CDCl₃, 400 MHz): δ 1.62 (m, 2H), 1.86 (m, 2H), 2.25-2.39 (m,9H), 3.63 (m, 4H), 3.70 (s, 3H), 4.07 (t, J=7.2 Hz, 2H), 6.30 (d, J=5.2Hz, 1H), 6.81 (s, 1H), 7.07 (d, J=7.4 Hz, 1H), 7.22-7.26 (m, 3H),7.34-7.39 (m, 3H), 7.62 (m, 2H), 8.32 (d, J=5.2 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 527 (M+1)⁺

Compound 150[2-({7-[4-(1-Imidazoyl)butoxy]-6-methoxy-4-quinolyl}-oxy)-5-methylphenyl](phenyl)methanone

(2-{[7-(4-Chlorobutoxy)-6-methoxy-4-quinolyl]oxy}-5-methylphenyl)(phenyl)methanone(60 mg), imidazole (27 mg), and potassium carbonate (90 mg) weresuspended in N,N-dimethylformamide (2 ml), and the suspension wasstirred at 80° C. overnight. The reaction solution was cooled to roomtemperature, water was then added to the reaction solution, and themixture was extracted with ethyl acetate. The ethyl acetate layer wasthen washed with water and saturated brine and was dried over anhydroussodium sulfate. The solvent was removed therefrom by distillation underthe reduced pressure, and the residue was purified by thin layerchromatography using methanol-chloroform to give the title compound (16mg, yield 24%).

¹H-NMR (CDCl₃, 400 MHz): δ 1.77 (m, 2H), 1.91 (m, 2H), 2.37 (s, 3H),3.70 (s, 3H), 3.99 (t, J=6.8 Hz, 2H), 4.14 (t, J=6.8 Hz, 2H), 6.30 (d,J=5.2 Hz, 1H), 6.81 (s, 1H), 6.88 (s, 1H), 6.98 (s, 1H), 7.07 (d, J=7.2Hz, 1H), 7.17-7.26 (m, 3H), 7.33-7.41 (m, 3H), 7.47 (m, 1H), 7.62 (m,2H), 8.30 (d, J=5.2 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 530 (M+Na)⁺

Compound 151(2-{[6-Methoxy-7-(2-oxiranylmethoxy)-4-quinolyl]oxy}-5-methylphenyl)(phenyl)methanone

{2-[(7-Hydroxy-6-methoxy-4-quinolyl)oxy]-5-methylphenyl}-(phenyl)methanone(200 mg), epibromohydrin (213 mg), and potassium carbonate (358 mg) weresuspended in N,N-dimethylformamide (5 ml), and the suspension wasstirred at room temperature overnight. Water was added to the reactionsolution, and the mixture was extracted with ethyl acetate. The ethylacetate layer was then washed with water and saturated brine and wasdried over anhydrous sodium sulfate. The solvent was removed therefromby distillation under the reduced pressure, and the residue was purifiedby thin layer chromatography using acetone-hexane to give the titlecompound (176 mg, yield 75%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.38 (s, 3H), 2.54-2.91 (m, 2H), 3.38 (m,1H), 3.72 (s, 3H), 4.00-4.30 (m, 2H), 6.31 (d, J=5.3 Hz, 1H), 6.81 (s,1H), 7.06 (d, J=7.2 Hz, 1H), 7.19-7.24 (m, 3H), 7.33-7.38 (m, 3H), 7.59(m, 2H), 8.33 (d, J=5.3 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 442 (M+1)⁺

Compound 152{2-[(7-{2-Hydroxy-3-[(2-hydroxyethyl)amino]propoxy}-6-methoxy-4-quinolyl)oxy]-5-methylphenyl}(phenyl)methanone

(2-{[6-Methoxy-7-(2-oxiranylmethoxy)-4-quinolyl]oxy}-5-methylphenyl)(phenyl)methanone(compound 151) (39 mg) and 4-aminoethanol (16 mg) were suspended inN,N-dimethylformamide (3 ml), and the suspension was stirred at 80° C.overnight. The reaction solution was cooled to room temperature, waterwas then added to the reaction solution, and the mixture was extractedwith ethyl acetate. The ethyl acetate layer was then washed with waterand saturated brine and was dried over anhydrous sodium sulfate. Thesolvent was removed therefrom by distillation under the reducedpressure, and the residue was purified by thin layer chromatographyusing methanol-chloroform to give the title compound (29 mg, yield 66%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.39 (s, 3H), 2.76-2.87 (m, 4H), 3.62-3.76(m, 5H), 4.06 (m, 2H), 4.19 (m, 1H), 6.31 (d, j=5.3 Hz, 1H), 6.79 (s,1H), 7.07 (d, J=7.2 Hz, 1H), 7.20-7.25 (m, 3H), 7.34-7.38 (m, 3H), 7.60(m, 2H), 8.31 (d, J=5.3 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 525 (M+Na)⁺

Compound 153[2-({7-[3-(Diethylamino)-2-hydroxypropoxy]-6-methoxy-4-quinolyl}oxy)-5-methylphenyl](phenyl)methanone

(2-{[6-Methoxy-7-(2-oxiranylmethoxy)-4-quinolyl]oxy}-5-methylphenyl)(phenyl)methanone(39 mg) and diethylamine (19 mg) were suspended in N,N-dimethylformamide(3 ml), and the suspension was stirred at 80° C. overnight. The reactionsolution was cooled to room temperature, water was then added to thereaction solution, and the mixture was extracted with ethyl acetate. Theethyl acetate layer was then washed with water and saturated brine andwas dried over anhydrous sodium sulfate. The solvent was removedtherefrom by distillation under the reduced pressure, and the residuewas purified by thin layer chromatography using methanol-chloroform togive the title compound (21 mg, yield 46%).

¹H-NMR (CDCl₃, 400 MHz): δ 1.02 (m, 6H), 2.39 (s, 3H), 2.48-2.70 (m,6H), 3.70 (s, 3H), 4.03 (m, 2H), 4.12 (m, 1H), 6.31 (d, J=5.4 Hz, 1H),6.81 (s, 1H), 7.07 (d, J=7.2 Hz, 1H), 7.20-7.26 (m, 3H), 7.34-7.40 (m,3H), 7.61 (m, 2H), 8.32 (d, J=5.4 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 515 (M+1)⁺

Compound 154{2-[(7-{2-Hydroxy-3-[4-(hydroxymethyl)piperidino]-propoxy}-6-methoxy-4-quinolyl)oxy]-5-methylphenyl}(phenyl)methanone

(2-{[6-Methoxy-7-(2-oxiranylmethoxy)-4-quinolyl]oxy}-5-methylphenyl)(phenyl)methanone(41 mg) and 4-piperidine ethanol (32 mg) were suspended inN,N-dimethylformamide (4 ml), and the suspension was stirred at 80° C.overnight. The reaction solution was cooled to room temperature, waterwas then added to the reaction solution, and the mixture was extractedwith ethyl acetate. The ethyl acetate layer was then washed with waterand saturated brine and was dried over anhydrous sodium sulfate. Thesolvent was removed therefrom by distillation under the reducedpressure, and the residue was purified by thin layer chromatographyusing methanol-chloroform to give the title compound (48 mg, yield 93%).

¹H-NMR (CDCl₃, 400 MHz): δ 1.68 (m, 2H), 1.99 (m, 2H), 2.25 (m, 1H),2.39 (s, 3H), 2.50 (m, 2H), 2.85-3.02 (m, 4H), 3.39-3.43 (m, 2H), 3.69(s, 3H), 4.02 (m, 2H), 4.17 (m, 1H), 6.31 (d, J=5.4 Hz, 1H), 6.79 (s,1H), 7.07 (d, J=7.3 Hz, 1H), 7.20-7.26 (m, 3H), 7.34-7.40 (m, 3H), 7.61(m, 2H), 8.32 (d, J=5.4 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 557 (M+1)⁺

Compound 155[2-({7-[2-Hydroxy-3-(4-tetrahydro-1-pyrrolylpiperidino)-propoxy]-6-methoxy-4-quinolyl}oxy)-5-methylphenyl](phenyl)methanone

(2-{[6-Methoxy-7-(2-oxiranylmethoxy)-4-quinolyl]oxy}-5-methylphenyl)(phenyl)methanone(39 mg) and 4-(1-pyrrolidinyl)piperidine (41 mg) were suspended inN,N-dimethylformamide (3 ml), and the suspension was stirred at 80° C.overnight. The reaction solution was cooled to room temperature, waterwas then added to the reaction solution, and the mixture was extractedwith ethyl acetate. The ethyl acetate layer was then washed with waterand saturated brine and was dried over anhydrous sodium sulfate. Thesolvent was removed therefrom by distillation under the reducedpressure, and the residue was purified by thin layer chromatographyusing methanol-chloroform to give the title compound (38 mg, yield 73%).

¹H-NMR (CDCl₃, 400 MHz): δ 1.46-1.59 (m, 2H), 1.72 (m, 4H), 1.82 (m,2H), 1.97 (m, 2H), 2.26 (m, 1H), 2.39 (s, 3H), 2.42-2.52 (m, 6H),2.78-2.96 (m, 2H), 3.69 (s, 3H), 4.03 (m, 2H), 4.11 (m, 1H), 6.30 (d,J=5.3 Hz, 1H), 6.79 (s, 1H), 7.07 (d, J=7.2 Hz, 1H), 7.20-7.25 (m, 3H),7.34-7.38 (m, 3H), 7.61 (m, 2H), 8.32 (d, J=5.3 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 596 (M+1)⁺

Compound 156[2-({7-[2-Hydroxy-3-(4-piperidylpiperidino)propoxy]-6-methoxy-4-quinolyl}oxy)-5-methylphenyl](phenyl)methanone

(2-{[6-Methoxy-7-(2-oxiranylmethoxy)-4-quinolyl]oxy}-5-methylphenyl)(phenyl)methanone(39 mg) and 4-piperidinopiperidine (45 mg) were suspended inN,N-dimethylformamide (3 ml), and the suspension was stirred at 80° C.overnight. The reaction solution was cooled to room temperature, waterwas then added to the reaction solution, and the mixture was extractedwith ethyl acetate. The ethyl acetate layer was then washed with waterand saturated brine and was dried over anhydrous sodium sulfate. Thesolvent was removed therefrom by distillation under the reducedpressure, and the residue was purified by thin layer chromatographyusing methanol-chloroform to give the title compound (49 mg, yield 91%).

¹H-NMR (CDCl₃, 400 MHz): δ 1.36 (m, 2H), 1.45-1.54 (m, 6H), 1.74 (m,2H), 1.93 (m, 1H), 2.21 (m, 2H), 2.39-2.50 (m, 9H), 2.83-3.00 (m, 2H),3.69 (s, 3H), 4.02 (m, 2H), 4.11 (m, 1H), 6.30 (d, J=5.4 Hz, 1H), 6.79(s, 1H), 7.07 (d, J=7.2 Hz, 1H), 7.20-7.25 (m, 3H), 7.34-7.38 (m, 3H),7.61 (m, 2H), 8.31 (d, J=5.4 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 610 (M+1)⁺

Compound 157[2-({7-[2-Hydroxy-3-(1-piperazino)propoxy]-6-methoxy-4-quinolyl}oxy)-5-methylphenyl](phenyl)methanone

(2-{[6-Methoxy-7-(2-oxiranylmethoxy)-4-quinolyl]oxy}-5-methylphenyl)(phenyl)methanone(39 mg) and piperazine (23 mg) were suspended in N,N-dimethylformamide(3 ml), and the suspension was stirred at 80° C. overnight. The reactionsolution was cooled to room temperature, water was then added to thereaction solution, and the mixture was extracted with ethyl acetate. Theethyl acetate layer was then washed with water and saturated brine andwas dried over anhydrous sodium sulfate. The solvent was removedtherefrom by distillation under the reduced pressure, and the residuewas purified by thin layer chromatography using methanol-chloroform togive the title compound (22 mg, yield 47%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.39-2.59 (m, 9H), 2.80-2.90 (m, 4H), 3.70(s, 3H), 4.04 (m, 2H), 4.15 (m, 1H), 6.31 (d, J=5.4 Hz, 1H), 6.80 (s,1H), 7.07 (d, J=7.2 Hz, 1H), 7.20-7.25 (m, 3H), 7.34-7.38 (m, 3H), 7.62(m, 2H), 8.32 (d, J=5.4 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 528 (M+1)⁺

Compound 158[2-({7-[2-Hydroxy-3-(4-methylpiperazino)propoxy]-6-methoxy-4-quinolyl}oxy)-5-methylphenyl](phenyl)methanone

(2-{[6-Methoxy-7-(2-oxiranylmethoxy)-4-quinolyl]oxy}-5-methylphenyl)(phenyl)methanone(39 mg) and 4-methylpiperazine (27 mg) were suspended inN,N-dimethylformamide (3 ml), and the suspension was stirred at 80° C.overnight. The reaction solution was cooled to room temperature, waterwas then added to the reaction solution, and the mixture was extractedwith ethyl acetate. The ethyl acetate layer was then washed with waterand saturated brine and was dried over anhydrous sodium sulfate. Thesolvent was removed therefrom by distillation under the reducedpressure, and the residue was purified by thin layer chromatographyusing methanol-chloroform to give the title compound (40 mg, yield 84%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.24 (s, 3H), 2.39-2.64 (m, 13H), 3.69 (s,3H), 4.04 (m, 2H), 4.15 (m, 1H), 6.31 (d, J=5.3 Hz, 1H), 6.79 (s, 1H),7.09 (d, J=7.2 Hz, 1H), 7.20-7.25 (m, 3H), 7.34-7.38 (m, 3H), 7.61 (m,2H), 8.32 (d, J=5.3 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 564 (M+Na)⁺

Compound 159(2-{[7-(2-Hydroxy-3-morpholinopropoxy)-6-methoxy-4-quinolyl]oxy}-5-methylphenyl)(phenyl)methanone

(2-{[6-Methoxy-7-(2-oxiranylmethoxy)-4-quinolyl]oxy}-5-methylphenyl)(phenyl)methanone(41 mg) and morpholine (53 mg) were suspended in N,N-dimethylformamide(4 ml), and the suspension was stirred at 80° C. overnight. The reactionsolution was cooled to room temperature, water was then added to thereaction solution, and the mixture was extracted with ethyl acetate. Theethyl acetate layer was then washed with water and saturated brine andwas dried over anhydrous sodium sulfate. The solvent was removedtherefrom by distillation under the reduced pressure, and the residuewas purified by thin layer chromatography using methanol-chloroform togive the title compound (34 mg, yield 69%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.39-2.62 (m, 9H), 3.62-3.70 (m, 7H), 4.05(m, 2H), 4.17 (m, 1H), 6.32 (d, J=5.4 Hz, 1H), 6.81 (s, 1H), 7.08 (d,J=7.3 Hz, 1H), 7.20-7.26 (m, 3H), 7.34-7.40 (m, 3H), 7.61 (m, 2H), 8.32(d, J=5.4 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 551 (M+Na)⁺

Compound 160[2-({7-[2-Hydroxy-3-(1-imidazoyl)propoxy]-6-methoxy-4-quinolyl}oxy)-5-methylphenyl](phenyl)methanone

(2-{[6-Methoxy-7-(2-oxiranylmethoxy)-4-quinolyl]oxy}-5-methylphenyl)(phenyl)methanone(39 mg) and imidazole (18 mg) were suspended in N,N-dimethylformamide (3ml), and the suspension was stirred at 80° C. overnight. The reactionsolution was cooled to room temperature, water was then added to thereaction solution, and the mixture was extracted with ethyl acetate. Theethyl acetate layer was then washed with water and saturated brine andwas dried over anhydrous sodium sulfate. The solvent was removedtherefrom by distillation under the reduced pressure, and the residuewas purified by thin layer chromatography using methanol-chloroform togive the title compound (36 mg, yield 80%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.39 (s, 3H), 3.70 (s, 3H), 3.86 (m, 1H),4.01-4.31 (m, 4H), 6.32 (d, J=5.3 Hz, 1H), 6.84-7.69 (m, 13H), 8.31 (d,J=5.3 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 532 (M+Na)⁺

Compound 161{2-[(6,7-Dimethoxy-4-quinazolyl)oxy]-5-methylphenyl}-(phenyl)methanone

4-Chloro-6,7-dimethoxyquinazoline (59 mg),2-hydroxy-5-methylbenzophenone (279 mg), and 4-dimethylaminopyridine(168 mg) were suspended in o-dichlorobenzene (5 ml), and the suspensionwas stirred at 160° C. for 10 min. The reaction solution was cooled toroom temperature, the solvent was then removed therefrom by distillationunder the reduced pressure, and chloroform was added to the residue. Themixture was washed with a 1 N aqueous potassium hydroxide solution andsaturated brine and was dried over anhydrous magnesium sulfate. Thesolvent was removed therefrom by distillation under the reducedpressure, and the residue was purified by column chromatography usingchloroform and by thin layer chromatography using acetone-hexane to givethe title compound (97 mg, yield 92%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.46 (s, 3H), 3.90 (s, 3H), 4.01 (s, 3H),7.03 (s, 1H), 7.19 (s, 1H), 7.22-7.27 (m, 2H), 7.31 (d, J=8.6 Hz, 1H),7.33-7.39 (m, 1H), 7.43-7.49 (m, 2H), 7.67-7.73 (m, 2H), 8.49 (s, 1H)

Mass spectrometric value (ESI−MS, m/z): 401 (M+1)⁺

Compound 1621-{2-[(6,7-Dimethoxy-4-quinazolyl)oxy]-5-methoxyphenyl}-1-ethanone

4-Chloro-6,7-dimethoxyquinazoline (59 mg),2-hydroxy-5-methoxyacetophenone (213 mg), and 4-dimethylaminopyridine(173 mg) were suspended in o-dichlorobenzene (5 ml), and the suspensionwas stirred at 160° C. for 10 min. The reaction solution was cooled toroom temperature, the solvent was then removed therefrom by distillationunder the reduced pressure, and chloroform was added to the residue. Themixture was washed with a 1 N aqueous potassium hydroxide solution andsaturated brine and was dried over anhydrous magnesium sulfate. Thesolvent was removed therefrom by distillation under the reducedpressure, and the residue was purified by column chromatography usingchloroform and by thin layer chromatography using acetone-hexane to givethe title compound (46.5 mg, yield 50%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.45 (s, 3H), 3.89 (s, 3H), 4.07 (s, 6H),7.13-7.20 (m, 2H), 7.34 (s, 1H), 7.40 (d, J=2.4 Hz, 1H), 7.56 (s, 1H),8.60 (s, 1H)

Mass spectrometric value (ESI−MS, m/z): 355 (M+1)⁺

Compound 163 Ethyl 2-[(6,7-dimethoxy-4-quinolyl)carbonyl]benzoate

6,7-Dimethoxyquinolone (0.79 g) was dissolved in chlorobenzene (7 ml) toprepare a solution. Phosphorus oxybromide (3.34 g) was added to thesolution, and the mixture was stirred at 150° C. for 6 hr. The reactionsolution was cooled to room temperature, water was then added to thereaction solution, and the mixture was extracted with ethyl acetate. Theethyl acetate layer was then washed with water and saturated brine andwas dried over anhydrous sodium sulfate. The solvent was removedtherefrom by distillation under the reduced pressure, and the residuewas purified by column chromatography on silica gel usingacetone-chloroform to give 4-bromo-6,7-dimethoxyquinoline (429 mg, yield42%).

4-Bromo-6,7-dimethoxyquinoline (138 mg) was dissolved in tetrahydrofuran(6 ml) to prepare a solution which was then cooled to −78° C. A 1.59 Mn-butyllithium/hexane solution (0.3 ml) was added to the cooledsolution, and the mixture was stirred at −78° C. for 20 min. A solutionof phthalic anhydride (250 mg) in tetrahydrofuran (2 ml) was added tothe reaction solution, and the mixture was stirred at room temperaturefor one hr. Water was added to the reaction solution, and the mixturewas extracted with ethyl acetate. The ethyl acetate layer was thenwashed with water and saturated brine and was dried over anhydroussodium sulfate. The solvent was removed therefrom by distillation underthe reduced pressure, and the residue was used in the next reactionwithout purification.

The residue provided by the above reaction was dissolved inN,N-dimethylformamide (1 ml) to prepare a solution, cesium carbonate(100 mg) and ethyl iodide (0.05 ml) were added to the solution, and themixture was stirred at room temperature for one hr. Water was added tothe reaction solution, and the mixture was extracted with ethyl acetate.The ethyl acetate layer was then washed with water and saturated brineand was dried over anhydrous sodium sulfate. The solvent was removedtherefrom by distillation under the reduced pressure, and the residuewas purified by thin layer chromatography using acetone-chloroform togive the title compound (3 mg, yield 2%) (2 steps).

¹H-NMR (CDCl₃, 400 MHz): δ 1.01 (t, J=7.1 Hz, 3H), 3.98 (q, J=7.1 Hz,2H), 4.07 (s, 3H), 4.07 (s, 3H), 7.07 (d, J=4.6 Hz, 1H), 7.51 (s, 1H),7.53 (dd, J=1.4 Hz, 7.3 Hz, 1H), 7.64 (m, 1H), 7.66 (m, 1H), 8.02 (m,1H), 8.33 (s, 1H), 8.69 (d, J=4.6 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 366 (M+1)⁺

Compound 164 4-(2-Iodo-4,5-dimethyl-phenoxy)-6,7-dimethoxy-quinoline

3,4-Dimethylphenol (0.68 g) and iodine (1.82 g) were dissolved inmethanol/water (10 ml/5 ml), and the mixture was stirred at roomtemperature overnight. An aqueous sodium sulfite solution was added tothe reaction solution, and the mixture was extracted with ethyl acetate.The ethyl acetate layer was then washed with water and was dried overanhydrous sodium sulfate. The solvent was removed by distillation underthe reduced pressure. The residue was purified by column chromatographyusing ethyl acetate-hexane to give 2-iodo-4,5-dimethylphenol (833 mg,yield 64%).

2-Iodo-4,5-dimethylphenol (447 mg), 4-chloro-6,7-dimethoxyquinoline (466mg), and 4-dimethylaminopyridine (539 mg) were suspended ino-dichlorobenzene (20 ml), and the mixture was stirred at 130° C. for 4hr. The reaction solution was cooled to room temperature, and thesolvent was then removed by distillation under the reduced pressure.Water was then added to the residue, and the mixture was extracted withchloroform. The chloroform layer was washed with water and was driedover anhydrous sodium sulfate. The solvent was removed by distillationunder the reduced pressure. The residue was purified by columnchromatography using acetone-chloroform to give the title compound (452mg, yield 50%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.25 (s, 3H), 2.28 (s, 3H), 4.05 (s, 3H),4.07 (s, 3H), 6.32 (d, J=5.4 Hz, 1H), 6.97 (s, 1H), 7.44 (s, 1H), 7.61(s, 1H), 7.68 (s, 1H), 8.48 (d, J=5.1 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 436 (M+1)⁺

Compound 1651-[2-(6,7-Dimethoxy-quinolin-4-yloxy)-5-methyl-phenyl]-decane-1,10-diol

4-Methylanisole (732 mg) was dissolved in nitromethane (30 ml) toprepare a solution. Anhydrous lithium perchlorate (3.8 g), methyl10-chloro-10-oxodecanoate (2 ml), and scandium triflate (300 mg) wereadded to the solution, and the mixture was stirred at room temperaturefor 4 hr. Water was added to the reaction solution, and the mixture wasextracted with ethyl acetate. The ethyl acetate layer was then washedwith water and was dried over anhydrous sodium sulfate. The solvent wasremoved by distillation under the reduced pressure, and the residue waspurified by column chromatography using acetone-hexane to give methyl10-(2-methoxy-5-methyl-phenyl)-10-oxo-decanoate (1.6 g, yield 83%).

Methyl 10-(2-methoxy-5-methyl-phenyl)-10-oxo-decanoate (1.6 g) wasdissolved in methylene chloride (30 ml), 1 M boron tribromide (7.5 ml)was added to the solution at −78° C., and the mixture was stirred atroom temperature for 30 min. Water was added to the reaction solution,and the mixture was extracted with chloroform, and the chloroform layerwas then washed with water and was dried over anhydrous sodium sulfate.The solvent was removed by distillation under the reduced pressure, andthe residue was purified by column chromatography using acetone-hexaneto give methyl 10-(2-hydroxy-5-methyl-phenyl)-10-oxo-decanoate (546 mg,yield 34%).

Methyl 10-(2-hydroxy-5-methyl-phenyl)-10-oxo-decanoate (546 mg),4-chloro-6,7-dimethoxyquinoline (397 mg), and 4-dimethylaminopyridine(434 mg) were suspended in o-dichlorobenzene (20 ml), and the suspensionwas stirred at 120° C. overnight. The reaction solution was cooled toroom temperature, and the solvent was removed by distillation under thereduced pressure. Water was then added to the residue, and the mixturewas extracted with chloroform. The chloroform layer was washed withwater and was dried over anhydrous sodium sulfate, and the solvent wasremoved by distillation under the reduced pressure. The residue waspurified by column chromatography using acetone-hexane to give methyl10-[2-(6,7-dimethoxy-quinolin-4-yloxy)-5-methyl-phenyl]-10-oxo-decanoate(90 mg, yield 10%).

Methyl10-[2-(6,7-dimethoxy-quinolin-4-yloxy)-5-methyl-phenyl]-10-oxo-decanoate(40 mg) was dissolved in tetrahydrofuran (3 ml), 0.93 Mdiisobutylaluminum hydride (1 ml) was added to the solution at 0° C.,and the mixture was stirred at room temperature for 5 hr. Water wasadded to the reaction solution, and the mixture was extracted with ethylacetate. The ethyl acetate layer was then washed with water and wasdried over anhydrous sodium sulfate. The solvent was removed bydistillation under the reduced pressure, and the residue was purified bythin layer chromatography using methanol-chloroform to give the titlecompound (4.9 mg, yield 13%).

¹H-NMR (CDCl₃, 400 MHz): δ 1.02-1.78 (m, 16H), 2.42 (s, 3H), 3.61 (t,J=6.6 Hz, 2H), 4.05 (s, 6H), 4.86 (m, 1H), 6.38 (d, J=5.4 Hz, 1H), 6.98(d, J=8.3 Hz, 1H), 7.16 (m, 1H), 7.45 (m, 2H), 7.56 (s, 1H), 8.39 (d,J=5.4 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 468 (M+1)⁺

Compound 1661-[2-(6,7-Dimethoxy-quinolin-4-yloxy)-5-methoxyphenyl]-2-pyridin-2-yl-ethanol

2-Picoline (40 μl) was dissolved in tetrahydrofuran (2 ml), and thesolution was cooled to −78° C. under an argon atmosphere. n-Butyllithium(1.56 M hexane solution) (260 μl) was added to the cooled solution, andthe mixture was stirred for 2 hr. A solution of2-(6,7-dimethoxy-quinolin-4-yloxy)-5-methoxy-benzaldehyde (100 mg) intetrahydrofuran (2 ml) was then added to the reaction solution, and themixture was stirred at −78° C. for one hr. A saturated ammonium chloridesolution was added to the reaction solution, and the mixture wasextracted with ethyl acetate. The ethyl acetate layer was then washedwith water and was dried over anhydrous sodium sulfate. The solvent wasremoved by distillation under the reduced pressure, and the residue waspurified by column chromatography using acetone-hexane to give the titlecompound (37 mg, yield 29%).

¹H-NMR (CDCl₃, 400 MHz): δ 3.01-3.14 (m, 2H), 3.86 (s, 3H), 4.02 (s,3H), 4.05 (s, 3H), 5.28 (m, 1H), 6.08 (brs, 1H), 6.45 (m, 1H), 6.80 (m,1H), 6.89 (m, 1H), 7.03 (m, 1H), 7.12 (m, 1H), 7.31 (d, J=3.0 Hz, 1H),7.43-7.53 (m, 2H), 7.57 (m, 1H), 8.46 (m, 2H)

Mass spectrometric value (ESI−MS, m/z): 433 (M+1)⁺

Compound 167 6,7-Dimethoxy-4-(4-methyl-2-pyridin-2-yl-phenoxy)-quinoline

N,N-dimethylformamide (1 ml) was added to4-(2-bromo-4-methyl-phenoxy)-6,7-dimethoxy-quinoline (compound 4) (50mg), tetrakistriphenylphosphine palladium (15 mg),tri-n-butyl-(2-pyridyl)-tin (59 mg), and copper(II) oxide (2.1 mg) underan argon atmosphere, and the mixture was stirred at 100° C. for 4 hr.The reaction solution was cooled to room temperature, water was thenadded thereto, and the mixture was extracted with ethyl acetate. Theethyl acetate layer was then washed with water and was dried overanhydrous sodium sulfate. The solvent was removed by distillation underthe reduced pressure, and the residue was purified by thin layerchromatography using acetone-hexane to give the title compound (37 mg,yield 75%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.48 (s, 3H), 4.04 (s, 3H), 4.05 (s, 3H),6.45 (d, J=5.6 Hz, 1H), 7.06-7.12 (m, 1H), 7.14 (d, J=8.0 Hz, 1H), 7.32(dd, J=2.2, 10.0 Hz, 1H), 7.45-7.58 (m, 3H), 7.60 (d, J=8.0 Hz, 1H),7.76 (s, 1H), 8.37 (d, J=5.6 Hz, 1H), 8.57 (d, J=4.6 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 373 (M+1)⁺

Compound 168 6,7-Dimethoxy-4-(4-methyl-2-pyridin-3-yl-phenoxy)-quinoline

N,N-Dimethylformamide (1 ml) and a 2 M aqueous potassium carbonatesolution (1 ml) were added to4-(2-bromo-4-methyl-phenoxy)-6,7-dimethoxy-quinoline (compound 4) (50mg), tetrakistriphenylphosphine palladium (15 mg), and 3-pyridylboronicacid (33 mg) under an argon atmosphere, and the mixture was stirred at70° C. for 5 hr. The reaction solution was cooled to room temperature,water was then added to the cooled reaction solution, and the mixturewas extracted with ethyl acetate. The ethyl acetate layer was thenwashed with water and was dried over anhydrous sodium sulfate. Thesolvent was removed therefrom by distillation under the reducedpressure. The residue was purified by thin layer chromatography usingchloroform-methanol to give the title compound (24.7 mg, yield 50%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.47 (s, 3H), 4.01 (s, 3H), 4.01 (s, 3H),6.37 (d, J=5.1 Hz, 1H), 7.15 (d, J=8.1 Hz, 1H), 7.16 (s, 1H), 7.69 (dd,J=1.5, 8.1 Hz, 1H), 7.34 (s, 1H), 7.36 (s, 1H), 7.43 (s, 1H), 7.76 (d,J=8.1 Hz, 1H), 8.28-8.58 (m, 2H), 8.77 (brs, 1H)

Mass spectrometric value (ESI−MS, m/z): 373 (M+1)⁺

Compound 1694-(4,5-Dimethyl-2-pyridin-2-yl-phenoxy)-6,7-dimethoxy-quinoline

4-(2-Iodo-4,5-dimethyl-phenoxy)-6,7-dimethoxy-quinoline (compound 164)(95 mg), tri-n-butyl(2-pyridyl)tin (0.25 ml), andtetrakistriphenylphosphine palladium (64 mg) were dissolved inN,N-dimethylformamide (7 ml), lithium chloride (102 mg) was added to thereaction system, and the mixture was stirred at 100° C. for one hr.Water was added to the reaction solution, and the mixture was extractedwith ethyl acetate. The ethyl acetate layer was then washed with waterand was dried over anhydrous sodium sulfate. The solvent was removed bydistillation under the reduced pressure. The residue was purified bythin layer chromatography using acetone-chloroform to give the titlecompound (3 mg, yield 4%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.33 (s, 3H), 2.38 (s, 3H), 4.03 (s, 3H),4.03 (s, 3H), 6.42 (d, J=5.4 Hz, 1H), 7.00 (s, 1H), 7.07 (dd, J=4.9, 7.6Hz, 1H), 7.39 (s, 1H), 7.45 (ddd, J=1.7, 7.6, 8.1 Hz, 1H), 7.54 (s, 1H),7.63 (d, J=8.1 Hz, 1H), 7.76 (s, 1H), 8.39 (d, J=5.4 Hz, 1H), 8.60 (d,J=4.9 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 387 (M+1)⁺

Compound 1704-(4,5-Dimethyl-2-pyridin-3-yl-phenoxy)-6,7-dimethoxy-quinoline

4-(2-Iodo-4,5-dimethyl-phenoxy)-6,7-dimethoxy-quinoline (compound 164)(59 mg), pyridine-3-boronic acid (33 mg), and tetrakistriphenylphosphinepalladium (10 mg) were dissolved in N,N-dimethylformamide (4 ml), a 2 Maqueous potassium carbonate solution (0.5 ml) was added to the reactionsystem, and the mixture was stirred at 100° C. for 30 min. Water wasadded to the reaction solution, and the mixture was extracted with ethylacetate. The ethyl acetate layer was then washed with water and wasdried over anhydrous sodium sulfate. The solvent was removed therefromby distillation under the reduced pressure. The residue was purified bythin layer chromatography using acetone-chloroform to give the titlecompound (13 mg, yield 25%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.33 (s, 3H), 2.37 (s, 3H), 4.01 (s, 3H),4.02 (s, 3H), 6.38 (d, J=5.4 Hz, 1H), 7.04 (s, 1H), 7.13 (dd, J=4.9, 8.1Hz, 1H), 7.30 (s, 1H), 7.36 (s, 1H), 7.44 (s, 1H), 7.55 (ddd, J=2.0,2.0, 7.8 Hz, 1H), 8.40-8.42 (m, 2H), 8.75 (d, J=2.2 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 387 (M+1)⁺

Compound 171 4-(4-Imidazol-1-yl-2-iodo-phenoxy)-6,7-dimethoxy-quinoline

4-(Imidazol-1-yl)phenol (500 mg) was dissolved in water (6 ml), methanol(18 ml), and dichloromethane (6 ml) to prepare a solution. Iodine (1.58g) was added to the solution, and the mixture was stirred at roomtemperature for 8 days. An aqueous sodium thiosulfate solution andmethanol were added to the reaction solution, and the mixture wasstirred and was then concentrated. The concentrate was extracted withchloroform, and the chloroform layer was then washed with water andsaturated brine and was dried over anhydrous sodium sulfate. The solventwas removed therefrom by distillation under the reduced pressure, andthe residue was purified by thin layer chromatography usingchloroform-methanol to give 4-(imidazol-1-yl)-2-iodophenol (123 mg,yield 14%).

4-(Imidazol-1-yl)-2-iodophenol (123 mg), 4-chloro-6,7-dimethoxyquinoline(288 mg), and 4-dimethylaminopyridine (158 mg) were suspended ino-dichlorobenzene (3 ml), and the suspension was stirred at 140° C. for7.5 hr. The reaction solution was cooled to room temperature, water wasthen added thereto, and the mixture was extracted with chloroform. Thechloroform layer was washed with saturated brine and was dried overanhydrous sodium sulfate. The solvent was removed therefrom bydistillation under the reduced pressure. The residue was purified bythin layer chromatography using chloroform-methanol to give the titlecompound (92 mg, yield 45%).

¹H-NMR (CDCl₃, 400 MHz): δ 4.07 (s, 3H), 4.08 (s, 3H), 6.42 (d, J=5.4Hz, 1H), 7.26-7.30 (m, 3H), 7.47-7.51 (m, 2H), 7.59 (s, 1H), 7.88 (s,1H), 7.99 (d, J=2.4 Hz, 1H), 8.53 (dd, J=0.7 Hz, 5.1 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 474 (M+1)⁺

Compound 1721-[2-(6,7-Dimethoxy-quinolin-4-yloxy)-5-ethyl-phenyl]-ethanone

3-Ethyl-6-hydroxyacetophenone (341 mg), 4-chloro-6,7-dimethoxyquinoline(154 mg), and 4-dimethylaminopyridine (254 mg) were suspended ino-dichlorobenzene (6.5 ml), and the suspension was stirred at 130° C.for 8 hr. The reaction solution was cooled to room temperature, waterwas then added to the reaction solution, and the mixture was extractedwith ethyl acetate. The ethyl acetate layer was then washed with waterand saturated brine and was dried over anhydrous sodium sulfate. Thesolvent was removed therefrom by distillation under the reducedpressure, and the residue was purified by thin layer chromatographyusing acetone-hexane to give the title compound (48 mg, yield 20%).

¹H-NMR (CDCl₃, 400 MHz): δ 1.21 (t, J=7.6 Hz, 3H), 2.44 (s, 3H), 2.65(q, J=7.6 Hz, 2H), 3.96 (s, 3H), 3.97 (s, 3H), 6.35 (d, J=5.6 Hz, 1H),7.00 (d, J=8.0 Hz, 1H), 7.32-7.37 (m, 2H), 7.48 (s, 1H), 7.67 (s, 1H),8.42 (d, J=5.6 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 352 (M+1)⁺

Compound 1731-[2-(6,7-Dimethoxy-quinolin-4-yloxy)-5-propyl-phenyl]-ethanone

4-n-Propylphenol (1.00 g) was dissolved in dichloromethane (10 ml) toprepare a solution. Pyridine (862 mg) and acetyl chloride (692 mg) wereadded to the solution, and the mixture was stirred at room temperatureovernight. The solvent was removed therefrom by distillation under thereduced pressure. Water was then added to the residue, and the mixturewas extracted with chloroform. The chloroform layer was washed withwater and was dried over anhydrous magnesium sulfate. The solvent wasremoved therefrom by distillation under the reduced pressure, and theresidue was purified by column chromatography using chloroform to give4-n-propylphenyl acetate (1.09 g, yield 100%).

4-n-Propylphenyl acetate (1.07 g) and scandium trifluoromethanesulfonate(345 mg) were suspended in toluene (10 ml), and the suspension wasstirred at 120° C. for 7 hr. The reaction solution was cooled to roomtemperature, and the cooled reaction solution was then filtered. Thesolvent was removed from the filtrate by distillation under the reducedpressure. Water was then added to the residue, and the mixture wasextracted with ethyl acetate. The ethyl acetate layer was then washedwith water and saturated brine and was dried over anhydrous sodiumsulfate. The solvent was removed therefrom by distillation under thereduced pressure, and the residue was purified by column chromatographyusing acetone-hexane to give 2-hydroxy-5-n-propylacetophenone (276 mg,yield 26%).

2-Hydroxy-5-n-propylacetophenone (276 mg),4-chloro-6,7-dimethoxyquinoline (117 mg), and 4-dimethylaminopyridine(191 mg) were suspended in o-dichlorobenzene (6.5 ml), and thesuspension was stirred at 130° C. for 8 hr. The reaction solution wascooled to room temperature, water was then added to the reactionsolution, and the mixture was extracted with ethyl acetate. The ethylacetate layer was then washed with water and saturated brine and wasdried over anhydrous sodium sulfate. The solvent was removed bydistillation under the reduced pressure. The residue was purified bythin layer chromatography using acetone-hexane to give the titlecompound (50 mg, yield 26%).

¹H-NMR (CDCl₃, 400 MHz): δ 0.90 (t, J=7.2 Hz, 3H), 1.61 (qt, J=7.2 Hz,J=7.6 Hz, 2H), 2.44 (s, 3H), 2.59 (t, J=7.6 Hz, 2H), 3.96 (s, 3H), 3.97(s, 3H), 6.35 (d, J=5.2 Hz, 1H), 7.00 (d, J=8.0 Hz, 1H), 7.30-7.37 (m,2H), 7.48 (s, 1H), 7.65 (s, 1H), 8.43 (d, J=5.2 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 366 (M+1)⁺

Compound 1741-[5-Butyl-2-(6,7-dimethoxy-quinolin-4-yloxy)-phenyl]-ethanone

4-n-Butylphenol (1.00 g) was dissolved in dichloromethane (10 ml) toprepare a solution. Pyridine (783 mg) and acetyl chloride (675 mg) wereadded to the solution, and the mixture was stirred at room temperatureovernight. The solvent was removed by distillation under the reducedpressure. Water was then added to the residue, and the mixture wasextracted with ethyl acetate. The ethyl acetate layer was then washedwith water and was dried over anhydrous magnesium sulfate. The solventwas removed by distillation under the reduced pressure. The residue waspurified by column chromatography using chloroform to give4-n-butylphenyl acetate (1.03 g, yield 80%).

4-n-Butylphenyl acetate (1.01 g) and scandium trifluoromethane sulfonate(307 mg) were suspended in toluene (10 ml) to prepare a suspension whichwas then stirred at 120° C. overnight. The reaction solution was cooledto room temperature and was then filtered. The solvent was removed fromthe filtrate by distillation under the reduced pressure, water was thenadded to the residue, and the mixture was extracted with ethyl acetate.The ethyl acetate layer was then washed with water and saturated brineand was dried over anhydrous sodium sulfate. The solvent was removed bydistillation under the reduced pressure. The residue was purified bycolumn chromatography using acetone-hexane to give3-n-butyl-6-hydroxyacetophenone (370 mg, yield 37%).

3-n-Butyl-6-hydroxyacetophenone (370 mg),4-chloro-6,7-dimethoxyquinoline (860 mg), and 4-dimethylaminopyridine(354 mg) were suspended in o-dichlorobenzene (5 ml) to prepare asuspension which was then stirred at 120° C. for 10 hr. The reactionsolution was cooled to room temperature, water was then added to thereaction solution, and the mixture was extracted with ethyl acetate. Theethyl acetate layer was then washed with water and saturated brine andwas dried over anhydrous sodium sulfate. The solvent was removed bydistillation under the reduced pressure. The residue was purified bythin layer chromatography using acetone-hexane to give the titlecompound (31 mg, yield 4%).

¹H-NMR (CDCl₃, 400 MHz): δ 0.88 (t, J=7.6 Hz, 3H), 1.31 (qt, J=7.6 Hz,J=7.6 Hz, 2H), 1.56 (tt, J=7.6 Hz, J=7.6 Hz, 2H), 2.44 (s, 3H), 2.61 (t,J=7.6 Hz, 2H), 3.96 (s, 3H), 3.98 (s, 3H), 6.35 (d, J=5.2 Hz, 1H), 6.99(d, J=7.8 Hz, 1H), 7.32 (dd, J=7.8 Hz, J=2.4 Hz, 1H), 7.37 (s, 1H), 7.48(s, 1H), 7.66 (d, J=2.4 Hz, 1H), 8.43 (d, J=5.2 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 380 (M+1)⁺

Compound 1751-[5-Benzyloxy-2-(6,7-dimethoxy-quinolin-4-yloxy)-phenyl]-ethanone

2,5-Dihydroxyacetophenone (3.00 g), benzyl bromide (2.48 g), andpotassium carbonate (8.16 g) were suspended in acetonitrile (30 ml) toprepare a suspension which was heated under reflux overnight. Thereaction solution was cooled to room temperature, and the solvent wasthen removed by distillation under the reduced pressure. Water was thenadded to the residue, and the mixture was extracted with chloroform. Thechloroform layer was washed with water and was dried over anhydrousmagnesium sulfate. The solvent was removed by distillation under thereduced pressure. The residue was purified by column chromatographyusing acetone-hexane to give 3-benzyloxy-6-hydroxyacetophenone (1.88 g,yield 39%).

3-Benzyloxy-6-hydroxyacetophenone (1.88 g),4-chloro-6,7-dimethoxyquinoline (3.43 g), and 4-dimethylaminopyridine(1.41 g) were suspended in o-dichlorobenzene (20 ml) to prepare asuspension which was then stirred at 130° C. for 10 hr. The reactionsolution was cooled to room temperature, water was then added to thereaction solution, and the mixture was extracted with ethyl acetate. Theethyl acetate layer was then washed with water and saturated brine andwas dried over anhydrous sodium sulfate. The solvent was removed bydistillation under the reduced pressure, and the residue was purified bycolumn chromatography using acetone-hexane to give the title compound(188 mg, yield 6%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.41 (s, 3H), 3.97 (s, 6H), 5.06 (s, 2H),6.31 (d, J=5.2 Hz, 1H), 7.02 (d, J=8.8 Hz, 1H), 7.13 (dd, J=8.8 Hz,J=3.2 Hz, 1H), 7.25-7.41 (m, 6H), 7.45 (d, J=3.2 Hz, 1H), 7.49 (s, 1H),8.41 (d, J=5.2 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 430 (M+1)⁺

Compound 1761-[2-(6,7-Dimethoxy-quinolin-4-yloxy)-5-hydroxy-phenyl]-ethanone

1-[5-Benzyloxy-2-(6,7-dimethoxy-quinolin-4-yloxy)-phenyl]-ethanone(compound 175) (188 mg) was suspended in a mixed solution composed ofmethanesulfonic acid (0.3 ml) and trifluoroacetic acid (4 ml) to preparea suspension which was then stirred at 70° C. for 1.5 hr. The solventwas removed by distillation under the reduced pressure, water was addedto the residue, and the mixture was neutralized with sodiumhydrogencarbonate powder and was then extracted with chloroform. Thechloroform layer was then washed with water and saturated brine and wasdried over anhydrous magnesium sulfate. The solvent was removed bydistillation under the reduced pressure. The residue was purified bycolumn chromatography using acetone-hexane to give the title compound(145 mg, yield 100%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.42 (s, 3H), 3.99 (s, 3H), 4.00 (s, 3H),6.41 (d, J=5.2 Hz, 1H), 7.01 (d, J=8.8 Hz, 1H), 7.12 (dd, J=8.8 Hz,J=2.8 Hz, 1H), 7.24 (s, 1H), 7.42 (m, 2H), 7.58 (s, 1H), 8.46 (d, J=5.2Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 340 (M+1)⁺

Compound 1771-[2-(6,7-Dimethoxy-quinolin-4-yloxy)-5-methoxy-phenyl]-ethanonehydrochloride

2-Hydroxy-5-methoxyacetophenone (11.1 g),4-chloro-6,7-dimethoxyquinoline (5.00 g), and 4-dimethylaminopyridine(8.10 g) were suspended in o-dichlorobenzene (40 ml) to prepare asuspension which was then stirred at 120° C. for 48 hr. The reactionsolution was cooled to room temperature, and the solvent was thenremoved by distillation under the reduced pressure. Water was added tothe residue, and the mixture was extracted with chloroform. Thechloroform layer was then washed with water and saturated brine and wasdried over anhydrous magnesium sulfate. The solvent was removed bydistillation under the reduced pressure. The residue was purified bycolumn chromatography using acetone-hexane to give1-[2-(6,7-dimethoxy-quinolin-4-yloxy)-5-methoxy-phenyl]-ethanone (802mg, yield 10%).

1-[2-(6,7-Dimethoxy-quinolin-4-yloxy)-5-methoxy-phenyl]-ethanone (802mg) was dissolved in a hydrochloric acid-methanol solution (20 ml) toprepare a solution which was then stirred at room temperature overnight.The solvent was removed by distillation under the reduced pressure, andthe residue was washed with ethyl acetate and was dried in vacuo to givethe title compound (885 mg, yield 100%).

¹H-NMR (CD₃OD, 400 MHz): δ 2.52 (s, 3H), 3.93 (s, 3H), 4.06 (s, 3H),4.12 (s, 3H), 6.78 (d, J=6.8 Hz, 1H), 7.38 (m, 2H), 7.45 (s, 1H), 7.59(d, J=2.8 Hz, 1H), 7.81 (s, 1H), 8.60 (d, J=6.8 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 354 (M+1-HCl)⁺

Compound 1781-[2-(6,7-Dimethoxy-quinolin-4-yloxy)-5-ethoxy-phenyl]-ethanone

1-[2-(6,7-Dimethoxy-quinolin-4-yloxy)-5-hydroxy-phenyl]-ethanone(compound 176) (75 mg) was dissolved in N,N-dimethylformamide (2 ml) toprepare a solution. Ethyl iodide (103 mg) and potassium carbonate (153mg) were added to the solution, and the mixture was stirred at roomtemperature overnight. The solvent was removed by distillation under thereduced pressure, water was then added to the residue, and the mixturewas extracted with ethyl acetate. The ethyl acetate layer was thenwashed with water and was dried over anhydrous magnesium sulfate. Thesolvent was removed by distillation under the reduced pressure, and theresidue was purified by thin layer chromatography using acetone-hexaneto give the title compound (50 mg, yield 62%).

¹H-NMR (CDCl₃, 400 MHz): δ 1.38 (t, J=6.8 Hz, 3H), 2.41 (s, 3H), 3.98(s, 6H), 4.04 (q, J=6.8 Hz, 2H), 6.30 (d, J=5.2 Hz, 1H), 7.00-7.07 (m,2H), 7.34 (d, J=2.8 Hz, 1H), 7.36 (s, 1H), 7.49 (s, 1H), 8.41 (d, J=5.2Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 368 (M+1)⁺

Compound 1791-[2-(6,7-Dimethoxy-quinolin-4-yloxy)-5-propoxy-phenyl]-ethanone

1-[2-(6,7-Dimethoxy-quinolin-4-yloxy)-5-hydroxy-phenyl]-ethanone(compound 176) (75 mg) was dissolved in N,N-dimethylformamide (2 ml) toprepare a solution. Propyl iodide (113 mg) and potassium carbonate (153mg) were added to the solution, and the mixture was stirred at roomtemperature overnight. The solvent was removed by distillation under thereduced pressure, water was then added to the residue, and the mixturewas extracted with ethyl acetate. The ethyl acetate layer was thenwashed with water and was dried over anhydrous magnesium sulfate. Thesolvent was removed by distillation under the reduced pressure, and theresidue was purified by thin layer chromatography using acetone-hexaneto give the title compound (22 mg, yield 26%).

¹H-NMR (CDCl₃, 400 MHz): δ 0.99 (t, J=7.4 Hz, 3H), 1.77 (m, 2H), 2.41(s, 3H), 3.92 (t, J=6.4 Hz, 2H), 3.98 (s, 6H), 6.30 (d, J=5.2 Hz, 1H),6.99-7.08 (m, 2H), 7.34 (d, J=2.8 Hz, 1H), 7.37 (s, 1H), 7.50 (s, 1H),8.41 (d, J=5.2 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 382 (M⁺+1)

Compound 1801-[5-Butoxy-2-(6,7-dimethoxy-quinolin-4-yloxy)-phenyl]-ethanone

1-[2-(6,7-Dimethoxy-quinolin-4-yloxy)-5-hydroxy-phenyl]-ethanone(compound 176) (54 mg) was dissolved in N,N-dimethylformamide (2 ml) toprepare a solution. Butyl iodide (88 mg) and potassium carbonate (110mg) were added to the solution, and the mixture was stirred at roomtemperature for 3 hr. The solvent was removed by distillation under thereduced pressure, water was then added to the residue, and the mixturewas extracted with ethyl acetate. The ethyl acetate layer was thenwashed with water and was dried over anhydrous magnesium sulfate. Thesolvent was removed by distillation under the reduced pressure, and theresidue was purified by thin layer chromatography using acetone-hexaneto give the title compound (41 mg, yield 65%).

¹H-NMR (CDCl₃, 400 MHz): δ 0.92 (t, J=7.4 Hz, 3H), 1.44 (m, 2H), 1.74(m, 2H), 2.41 (s, 3H), 3.93-4.05 (m, 8H), 6.30 (d, J=5.2 Hz, 1H),6.98-7.12 (m, 2H), 7.34 (d, J=3.2 Hz, 1H), 7.37 (s, 1H), 7.49 (s, 1H),8.41 (d, J=5.2 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 396 (M+1)⁺

Compound 1811-[4-Chloro-2-(6,7-dimethoxy-quinolin-4-yloxy)-phenyl]-ethanone

4-Chloro-2-hydroxyacetophenone (45 mg), 4-chloro-6,7-dimethoxyquinoline(60 mg), and 4-dimethylaminopyridine (95 mg) are suspended ino-dichlorobenzene (10 ml) to prepare a suspension which was then stirredat 120° C. overnight and then at 140° C. for 5 hr. The reaction solutionwas cooled to room temperature, and the solvent was removed bydistillation under the reduced pressure. Water was then added to theresidue, and the mixture was extracted with chloroform. The chloroformlayer was washed with water and was dried over anhydrous sodium sulfate,and the solvent was removed by distillation under the reduced pressure,and the residue was purified by thin layer chromatography usingacetone-hexane to give the title compound (11 mg, yield 12%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.54 (s, 3H), 4.04 (s, 3H), 4.07 (s, 3H),6.51 (d, J=5.4 Hz, 1H), 7.14 (d, J=2.0 Hz, 1H), 7.35 (dd, J=2.0 Hz, 8.6Hz, 1H), 7.48 (m, 2H), 7.91 (d, J=8.5 Hz, 1H), 8.57 (d, J=5.4 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 358 (M+1)⁺

Compound 182 1-[6-(6,7-Dimethoxy-quinolin-4-yloxy)-indan-5-yl]-ethanone

5-Indanol (500 mg) was dissolved in dichloromethane (5 ml) to prepare asolution. Pyridine (439 mg) and acetyl chloride (349 mg) were added tothe solution, and the mixture was stirred at room temperature for 6 hr.The solvent was removed by distillation under the reduced pressure,water was then added to the residue, and the mixture was extracted withethyl acetate. The ethyl acetate layer was then washed with water andwas dried over anhydrous magnesium sulfate. The solvent was removed bydistillation under the reduced pressure, and the residue was purified bycolumn chromatography using chloroform to give indan-5-yl acetate (599mg, yield 92%).

Indan-5-yl acetate (599 mg) and scandium trifluoromethane sulfonate (201mg) were suspended in toluene (5 ml), and the suspension was stirred at140° C. overnight. The reaction solution was cooled to room temperatureand was then filtered. The solvent was removed from the filtrate bydistillation under the reduced pressure, water was then added to theresidue, and the mixture was extracted with ethyl acetate. The ethylacetate layer was then washed with water and saturated brine and wasdried over anhydrous sodium sulfate. The solvent was removed bydistillation under the reduced pressure, and the residue was purified bycolumn chromatography using acetone-hexane to give1-(6-hydroxyindan-5-yl)-ethanone (275 mg, yield 46%).

1-(6-Hydroxyindan-5-yl)-ethanone (275 mg),4-chloro-6,7-dimethoxyquinoline (173 mg), and 4-dimethylaminopyridine(286 mg) were suspended in o-dichlorobenzene (5 ml) to prepare asuspension which was stirred at 130° C. overnight. The reaction solutionwas cooled to room temperature, water was then added to the reactionsolution, and the mixture was extracted with ethyl acetate. The ethylacetate layer was then washed with water and saturated brine and wasdried over anhydrous sodium sulfate. The solvent was removed bydistillation under the reduced pressure, and the residue was purified bythin layer chromatography using acetone-hexane to give the titlecompound (37 mg, yield 13%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.09 (m, 2H), 2.41 (s, 3H), 2.82-2.92 (m,4H), 3.97 (s, 6H), 6.35 (d, J=5.2 Hz, 1H), 6.91 (s, 1H), 7.37 (s, 1H),7.48 (s, 1H), 7.70 (s, 1H), 8.42 (d, J=5.2 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 364 (M+1)⁺

Compound 1831-[2-(6,7-Dimethoxy-quinolin-4-yloxy)-5-isopropyl-4-methyl-phenyl]-ethanone

4-Isopropyl-3-methylphenol (1.00 g) was dissolved in dichloromethane (10ml) to prepare a solution. Pyridine (724 mg) and acetyl chloride (615mg) were added to the solution, and the mixture was stirred at roomtemperature overnight. The solvent was removed by distillation under thereduced pressure, water was then added to the residue, and the mixturewas extracted with chloroform. The chloroform layer was washed withwater and was dried over anhydrous magnesium sulfate, and the solventwas removed by distillation under the reduced pressure. The residue wasdried under the reduced pressure to give 4-isopropyl-3-methylphenylacetate (1.41 g, yield 100%).

4-Isopropyl-3-methylphenyl acetate (1.41 g) and scandiumtrifluoromethane sulfonate (433 mg) were suspended in toluene (5 ml) toprepare a suspension which was then stirred at 140° C. overnight. Thereaction solution was cooled to room temperature and was filtered, andthe solvent was then removed from the filtrate by distillation under thereduced pressure. Water was then added to the residue, and the mixturewas extracted with ethyl acetate. The ethyl acetate layer was thenwashed with water and saturated brine and was dried over anhydroussodium sulfate. The solvent was removed by distillation under thereduced pressure, and the residue was purified by column chromatographyusing acetone-hexane to give1-(2-hydroxy-5-isopropyl-4-methyl-phenyl)-ethanone (13 mg, yield 1%).

1-(2-Hydroxy-5-isopropyl-4-methyl-phenyl)-ethanone (13 mg),4-chloro-6,7-dimethoxyquinoline (30 mg), and 4-dimethylaminopyridine (25mg) were suspended in o-dichlorobenzene (3 ml) to prepare a suspensionwhich was then stirred at 130° C. overnight. The reaction solution wascooled to room temperature, water was then added to the reactionsolution, and the mixture was extracted with ethyl acetate. The ethylacetate layer was then washed with water and saturated brine and wasdried over anhydrous sodium sulfate. The solvent was removed bydistillation under the reduced pressure, and the residue was purified bythin layer chromatography using acetone-hexane to give the titlecompound (2 mg, yield 7%).

¹H-NMR (CDCl₃, 400 MHz): δ 1.23 (d, J=7.2 Hz, 6H), 2.33 (s, 3H), 2.42(s, 3H), 3.10 (m, 1H), 3.98 (s, 3H), 4.03 (s, 3H), 6.42 (d, J=5.6 Hz,1H), 6.88 (s, 1H), 7.19 (s, 1H), 7.47 (s, 1H), 7.77 (s, 1H), 8.41 (d,J=5.6 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 380 (M+1)⁺

Compound 1841-[4-Chloro-2-(6,7-dimethoxy-quinolin-4-yloxy)-5-methyl-phenyl]-ethanone

3-Chloro-4-methylphenol (1.00 g) was dissolved in dichloromethane (10ml) to prepare a solution. Pyridine (747 mg) and acetyl chloride (656mg) were added to the solution, and the mixture was stirred at roomtemperature overnight. The solvent was removed by distillation under thereduced pressure, water was then added to the residue, and the mixturewas extracted with chloroform. The chloroform layer was washed withwater and was dried over anhydrous magnesium sulfate, and the solventwas then removed by distillation under the reduced pressure. The residuewas dried under the reduced pressure. Scandium trifluoromethanesulfonate(414 mg) was added to the compound thus obtained, and the mixture wassuspended in toluene (5 ml) to prepare a suspension which was thenheated under reflux overnight. The reaction solution was cooled to roomtemperature, and the reaction solution was then filtered. The solventwas removed from the filtrate by distillation under the reducedpressure, water was then added to the residue, and the mixture wasextracted with ethyl acetate. The ethyl acetate layer was then washedwith water and saturated brine and was dried over anhydrous sodiumsulfate. The solvent was removed by distillation under the reducedpressure, and the residue was purified by column chromatography usingacetone-hexane to give 1-(4-chloro-2-hydroxy-5-methyl-phenyl)-ethanone(193 mg, yield 15%).

1-(4-Chloro-2-hydroxy-5-methyl-phenyl)-ethanone (193 mg),4-chloro-6,7-dimethoxyquinoline (468 mg), and 4-dimethylaminopyridine(385 mg) were suspended in o-dichlorobenzene (5 ml) to prepare asuspension which was then stirred at 140° C. for 24 hr. The reactionsolution was cooled to room temperature, water was then added to thereaction solution, and the mixture was extracted with ethyl acetate. Theethyl acetate layer was then washed with water and saturated brine andwas dried over anhydrous magnesium sulfate. The solvent was removed bydistillation under the reduced pressure, and the residue was purified bythin layer chromatography using acetone-hexane to give the titlecompound (39 mg, yield 10%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.36 (s, 3H), 2.43 (s, 3H), 3.96 (s, 3H),3.98 (s, 3H), 6.39 (d, J=5.2 Hz, 1H), 7.09 (s, 1H), 7.39 (s, 1H), 7.43(s, 1H), 7.75 (s, 1H), 8.46 (d, J=5.2 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 372 (M+1)⁺

Compound 1851-[4-Tert-butyl-2-(6,7-dimethoxy-quinolin-4-yloxy)-5-methoxyphenyl]-ethanone

3-Tert-butyl-4-methoxyphenol (1.00 g) was dissolved in dichloromethane(10 ml) to prepare a solution. Pyridine (658 mg) and acetyl chloride(599 mg) were added to the solution, and the mixture was stirred at roomtemperature overnight. The solvent was removed by distillation under thereduced pressure, water was then added to the residue, and the mixturewas extracted with chloroform. The chloroform layer was washed withwater and was dried over anhydrous magnesium sulfate, and the solventwas then removed by distillation under the reduced pressure. The residuewas dried under the reduced pressure. Scandium trifluoromethanesulfonate (327 mg) was added to the compound thus obtained, the mixturewas suspended in toluene (5 ml), and the suspension was heated underreflux overnight. The reaction solution was cooled to room temperature,and the reaction solution was then filtered. The solvent was removedfrom the filtrate by distillation under the reduced pressure, water wasthen added to the residue, and the mixture was extracted with ethylacetate. The ethyl acetate layer was then washed with water andsaturated brine and was dried over anhydrous sodium sulfate. The solventwas removed by distillation under the reduced pressure, and the residuewas purified by column chromatography using acetone-hexane to give1-(4-tert-butyl-2-hydroxy-5-methoxy-phenyl)-ethanone (30 mg, yield 5%).

1-(4-Tert-butyl-2-hydroxy-5-methoxyphenyl)-ethanone (30 mg),4-chloro-6,7-dimethoxyquinoline (87 mg), and 4-dimethylaminopyridine (48mg) were suspended in o-dichlorobenzene (4 ml) to prepare a suspensionwhich was then stirred at 140° C. for 24 hr. The reaction solution wascooled to room temperature, water was then added to the reactionsolution, and the mixture was extracted with ethyl acetate. The ethylacetate layer was then washed with water and saturated brine and wasdried over anhydrous magnesium sulfate. The solvent was removed bydistillation under the reduced pressure, and the residue was purified bythin layer chromatography using acetone-hexane to give the titlecompound (7 mg, yield 13%).

¹H-NMR (CDCl₃, 400 MHz): δ 1.29 (s, 9H), 2.39 (s, 3H), 3.87 (s, 3H),3.99 (s, 6H), 6.29 (d, J=5.6 Hz, 1H), 7.00 (s, 1H), 7.39 (s, 1H), 7.44(s, 1H), 7.53 (s, 1H), 8.42 (d, J=5.6 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 410 (M+1)⁺

Compound 1861-[2-(6,7-Dimethoxy-quinolin-4-yloxy)-4-methyl-5-methylsulfanyl-phenyl]-ethanone

3-Methyl-4-methylsulfanylphenol (1.00 g) was dissolved indichloromethane (10 ml) to prepare a solution. Pyridine (724 mg) andacetyl chloride (615 mg) were added to the solution, and the mixture wasstirred at room temperature overnight. The solvent was removed bydistillation under the reduced pressure. Water was then added to theresidue, and the mixture was extracted with chloroform. The chloroformlayer was washed with water and was dried over anhydrous magnesiumsulfate. The solvent was removed by distillation under the reducedpressure. The residue was purified by column chromatography usingchloroform to give 3-methyl-4-methylsulfanyl-phenyl acetate (1.00 g,yield 80%).

3-Methyl-4-methylsulfanyl-phenyl acetate (1.00 g) and scandiumtrifluoromethane sulfonate (300 mg) were suspended in toluene (5 ml) toprepare a suspension which was heated under reflux overnight. Thesuspension was cooled to room temperature, and the reaction solution wasthen filtered. The solvent was removed from the filtrate by distillationunder the reduced pressure, water was then added to the residue, and themixture was extracted with ethyl acetate. The ethyl acetate layer wasthen washed with water and saturated brine and was dried over anhydroussodium sulfate. The solvent was removed by distillation under thereduced pressure, and the residue was purified by thin layerchromatography using acetone-hexane to give1-(2-hydroxy-4-methyl-5-methylsulfanyl-phenyl)-ethanone (150 mg, yield15%).

1-(2-Hydroxy-4-methyl-5-methylsulfanyl-phenyl)-ethanone (29 mg),4-chloro-6,7-dimethoxyquinoline (66 mg), and 4-dimethylaminopyridine (54mg) were suspended in o-dichlorobenzene (2 ml) to prepare a suspensionwhich was then stirred at 130° C. overnight. The reaction solution wascooled to room temperature, water was then added to the reactionsolution, and the mixture was extracted with ethyl acetate. The ethylacetate layer was then washed with water and saturated brine and wasdried over anhydrous magnesium sulfate. The solvent was removed bydistillation under the reduced pressure, and the residue was purified bythin layer chromatography using acetone-hexane to give the titlecompound (17 mg, yield 30%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.27 (s, 3H), 2.35 (s, 3H), 2.46 (s, 3H),3.98 (s, 6H), 6.30 (d, J=5.6 Hz, 1H), 6.88 (s, 1H), 7.11 (s, 1H), 7.39(s, 1H), 7.53 (s, 1H), 8.49 (d, J=5.6 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 767 (2M+1)⁺

Compound 187 Methyl8-[2-(6,7-dimethoxy-quinolin-4-yloxy)-5-methyl-phenyl]-8-oxo-octanoate

4-Methylanisole (732 mg) was dissolved in nitromethane (30 ml) toprepare a solution. Anhydrous lithium perchlorate (3.8 g), methyl7-chlorocarbonyl-heptanoate (1.28 ml), and scandium triflate (300 mg)were added to the solution, and the mixture was stirred at roomtemperature for 4 hr. Water was added to the reaction solution, and themixture was extracted with ethyl acetate. The ethyl acetate layer wasthen washed with water and was dried over anhydrous sodium sulfate. Thesolvent was removed by distillation under the reduced pressure, and theresidue was purified by column chromatography using acetone-hexane togive methyl 8-(2-methoxy-5-methyl-phenyl)-8-oxo-octanoate (992 mg, yield57%).

Methyl 8-(2-methoxy-5-methyl-phenyl)-8-oxo-octanoate (992 mg) wasdissolved in methylene chloride (30 ml) to prepare a solution. 1 M borontribromide (5.0 ml) was added at −78° C. to the solution, and themixture was stirred at room temperature for 30 min. Water was added tothe reaction solution, and the mixture was extracted with chloroform.The chloroform layer was then washed with water and was dried overanhydrous sodium sulfate. The solvent was removed by distillation underthe reduced pressure. The residue was purified by column chromatographyusing acetone-hexane to give methyl8-(2-hydroxy-5-methyl-phenyl)-8-oxo-octanoate (271 mg, yield 29%).

Methyl 8-(2-hydroxy-5-methyl-phenyl)-8-oxo-octanoate (271 mg),4-chloro-6,7-dimethoxyquinoline (220 mg), and 4-dimethylaminopyridine(237 mg) were suspended in o-dichlorobenzene (20 ml) to prepare asuspension which was then stirred at 120° C. overnight. The reactionsolution was cooled to room temperature, and the solvent was removed bydistillation under the reduced pressure. Water was then added to theresidue, and the mixture was extracted with chloroform. The chloroformlayer was washed with water and was dried over anhydrous sodium sulfate.The solvent was removed by distillation under the reduced pressure, andthe residue was purified by column chromatography using acetone-hexaneto give the title compound (16 mg, yield 3.5%).

¹H-NMR (CDCl₃, 400 MHz): δ 1.13 (m, 4H), 1.47 (m, 2H), 1.56 (m, 2H),2.17 (t, J=7.6 Hz, 2H), 2.44 (s, 3H), 2.83 (t, J=7.3 Hz, 2H), 3.63 (s,3H), 4.05 (s, 3H), 4.06 (s, 3H), 6.40 (d, J=5.4 Hz, 1H), 7.05 (d, J=8.3Hz, 1H), 7.37 (dd, J=2.2 Hz, 8.3 Hz, 1H), 7.45 (s, 1H), 7.54 (s, 1H),7.63 (d, J=2.0 Hz, 1H), 8.49 (d, J=5.4 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 466 (M+1)⁺

Compound 188[2-(6,7-Dimethoxy-quinolin-4-yloxy)-5-methyl-phenyl]-(4-hydroxy-phenyl)-methanone

4-Bromophenol (1.00 g) was dissolved in N,N-dimethylformamide (20 ml) toprepare a solution. Imidazole (0.95 g) andtert-butylchlorodimethylsilane (1.05 g) were added to the solution, andthe mixture was stirred at room temperature overnight. Water was addedto the reaction solution, and the mixture was extracted with ethylacetate. The ethyl acetate layer was then washed with water andsaturated brine and was dried over anhydrous sodium sulfate. The solventwas removed by distillation under the reduced pressure, and the residuewas purified by column chromatography using chloroform to give(4-bromo-phenoxy)-tert-butyl-dimethyl-silane (1.586 g, yield 96%).

2-Hydroxy-5-methyl-benzaldehyde (344 mg),4-chloro-6,7-dimethoxyquinoline (113 mg), and 4-dimethylaminopyridine(313 mg) were suspended in o-dichlorobenzene (5 ml), and the suspensionwas stirred at 160° C. for 2 hr. The reaction solution was cooled toroom temperature, and the solvent was removed by distillation under thereduced pressure. Water was then added to the residue, and the mixturewas extracted with chloroform. The chloroform layer was washed withaqueous sodium hydroxide solution and saturated brine and was dried overanhydrous magnesium sulfate. The solvent was removed by distillationunder the reduced pressure, and the residue was purified by columnchromatography using chloroform to give2-(6,7-dimethoxy-quinolin-4-yloxy)-5-methyl-benzaldehyde (157 mg, yield96%).

(4-Bromo-phenoxy)-tert-butyl-dimethyl-silane (175 mg) was dissolved intetrahydrofuran (3 ml) to prepare a solution which was cooled to −78° C.A 1.41 M n-pentane solution (0.86 ml) of tert-butyllithium was addeddropwise to the cooled solution, and the mixture was stirred at −78° C.for 20 min. A solution of2-(6,7-dimethoxy-quinolin-4-yloxy)-5-methyl-benzaldehyde (164 mg) intetrahydrofuran was added dropwise thereto, and the mixture was stirredat −78° C. for one hr and then at 0° C. for 30 min. A saturated ammoniumchloride solution was added thereto to stop the reaction, and themixture was then extracted with ethyl acetate. The ethyl acetate layerwas then washed with saturated brine and was dried over anhydrous sodiumsulfate. The solvent was removed by distillation under the reducedpressure, and the residue as such was used for the next reaction.

The residue (252 mg) of the reaction was dissolved in methylene chloride(5 ml) to prepare a solution. A solution of1,8-diazabicyclo[5.4.0]undeca-7-ene (154 mg) in methylene chloride wasadded to the solution, and the mixture was cooled to −78° C. A solutionof N-tert-butylbenzenesulfineimidoyl (164 mg) in methylene chloride wasadded thereto, and the mixture was stirred at −78° C. for one hr.Further, a solution of N-tert-butylbenzenesulfineimidoyl (55 mg) inmethylene chloride was added thereto, and the mixture was stirred at−78° C. for 30 min and then at 0° C. for 20 min. Water was added to thereaction solution, and the mixture was extracted with chloroform. Thechloroform layer was then washed with saturated brine and was dried overanhydrous sodium sulfate. The solvent was removed by distillation underthe reduced pressure, and the residue as such was used for the nextreaction.

A part (384 mg) of the residue of the reaction was dissolved intetrahydrofuran (5 ml) to prepare a solution which was cooled to 0° C. Asolution (1 ml) of tetrabutylammonium fluoride in tetrahydrofuran wasthen added thereto, and the mixture was stirred for 30 min. Water wasadded to the reaction solution, and the mixture was extracted with ethylacetate. The ethyl acetate layer was then washed with saturated brineand was dried over anhydrous magnesium sulfate. The solvent was removedby distillation under the reduced pressure, and the residue was purifiedby column chromatography using acetone-hexane to give the title compound(128 mg, yield 61%) (3 steps).

¹H-NMR (CDCl₃, 400 MHz): δ 2.45 (s, 3H), 3.86 (s, 3H), 3.88 (s, 3H),6.44 (d, J=5.4 Hz, 1H), 6.77 (d, J=8.8 Hz, 2H), 7.07 (s, 1H), 7.14 (d,J=8.0 Hz, 1H), 7.25 (s, 1H), 7.38-7.41 (m, 2H), 7.62 (d, J=8.8 Hz, 2H),8.33 (d, J=5.4 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 416 (M+1)⁺

Compound 189[4-(2-Chloro-ethoxy)-phenyl]-[2-(6,7-dimethoxy-quinolin-4-yloxy)-5-methyl-phenyl]-methanone

[2-(6,7-Dimethoxy-quinolin-4-yloxy)-5-methyl-phenyl]-(4-hydroxy-phenyl)-methanone(compound 188) (128 mg) was dissolved in N,N-dimethylformamide toprepare a solution. Potassium carbonate (215 mg) and1-bromo-2-chloroethane (134 mg) were then added to the solution, and themixture was stirred at room temperature overnight. Water was added tothe reaction solution, and the mixture was extracted with ethyl acetate.The ethyl acetate layer was then washed with water and saturated brineand was dried over anhydrous sodium sulfate. The solvent was removed bydistillation under the reduced pressure, and the residue was purified bycolumn chromatography using acetone-hexane to give the title compound(99 mg, yield 69%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.46 (s, 3H), 3.79 (t, J=5.9 Hz, 2H), 3.84(s, 3H), 3.99 (s, 3H), 4.19 (t, J=5.9 Hz, 2H), 6.40 (d, J=5.4 Hz, 1H),6.80 (d, J=8.8 Hz, 2H), 6.94 (s, 1H), 7.16 (d, J=8.1 Hz, 1H), 7.32 (s,1H), 7.40-7.44 (m, 2H), 7.68 (d, J=8.8 Hz, 2H), 8.41 (d, J=5.4 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 478 (M+1)⁺

Compound 190[2-(6,7-Dimethoxy-quinolin-4-yloxy)-5-methyl-phenyl]-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-methanone

[4-(2-Chloro-ethoxy)-phenyl]-[2-(6,7-dimethoxy-quinolin-4-yloxy)-5-methyl-phenyl]-methanone(compound 189) (48 mg) was dissolved in N,N-dimethylformamide to preparea solution. Potassium carbonate (86 mg) and piperidine (52 mg) were thenadded to the solution, and the mixture was stirred at 80° C. overnight.The reaction solution was cooled to room temperature, and water was thenadded to the reaction solution, and the mixture was extracted with ethylacetate. The ethyl acetate layer was then washed with water andsaturated brine and was dried over anhydrous sodium sulfate. The solventwas removed by distillation under the reduced pressure, and the residuewas purified by column chromatography using chloroform methanol to givethe title compound (31 mg, yield 58%).

¹H-NMR (CDCl₃, 400 MHz): δ 1.40-1.73 (m, 6H), 2.46 (s, 3H), 3.33-3.48(m, 4H), 3.83 (s, 3H), 3.99 (s, 3H), 4.17 (t, J=4.6 Hz, 2H), 4.41 (t,J=4.6 Hz, 2H), 6.42 (d, J=5.4 Hz, 1H), 6.84 (d, J=8.8 Hz, 2H), 6.98 (s,1H), 7.15 (d, J=8.6 Hz, 1H), 7.33 (s, 1H), 7.38-7.43 (m, 2H), 7.71 (d,J=8.8 Hz, 2H), 8.41 (d, J=5.4 Hz, 1H)

Compound 191[2-(6,7-Dimethoxy-quinolin-4-yloxy)-5-methyl-phenyl]-[4-(2-morpholin-4-yl-ethoxy)-phenyl]-methanone

[4-(2-Chloro-ethoxy)-phenyl]-[2-(6,7-dimethoxy-quinolin-4-yloxy)-5-methyl-phenyl]-methanone(compound 189) (51 mg) was dissolved in N,N-dimethylformamide to preparea solution. Potassium carbonate (84 mg) and morpholine (46 mg) were thenadded to the solution, and the mixture was stirred at 80° C. overnight.The reaction solution was cooled to room temperature, and water was thenadded to the reaction solution, and the mixture was extracted with ethylacetate. The ethyl acetate layer was then washed with water andsaturated brine and was dried over anhydrous sodium sulfate. The solventwas removed by distillation under the reduced pressure, and the residuewas purified by column chromatography using chloroform-methanol to givethe title compound (38 mg, yield 68%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.49 (s, 3H), 3.46 (brs, 4H), 3.64 (brs, 4H),3.84 (s, 3H), 3.99 (s, 3H), 4.16 (t, d=4.9 Hz, 2H), 4.44 (t, d=4.9 Hz,2H), 6.41 (d, J=5.4 Hz, 1H), 6.82 (d, J=8.8 Hz, 2H), 6.98 (s, 1H), 7.15(d, J=7.8 Hz, 1H), 7.32 (s, 1H), 7.41 (d, J=7.8 Hz, 1H), 7.42 (s, 1H),7.70 (d, J=8.8 Hz, 2H), 8.41 (d, J=5.4 Hz, 1H)

Compound 192[2-(6,7-Dimethoxy-quinolin-4-yloxy)-5-methoxy-phenyl]-thiazol-2-yl-methanone

Thiazole (30 μl) was dissolved in tetrahydrofuran (1 ml) to prepare asolution which was cooled under an argon atmosphere to −78° C.n-Butyllithium (1.56 M hexane solution) (260 μl) was added to the cooledsolution, and the mixture was stirred for 2 hr. A solution (2 ml) of2-(6,7-dimethoxy-quinolin-4-yloxy)-5-methoxy-benzaldehyde (compound 26)(138 mg) in tetrahydrofuran was then added to the reaction solution, andthe mixture was stirred at −78° C. for one hr. A saturated ammoniumchloride solution was added to the reaction solution, and the mixturewas extracted with ethyl acetate. The ethyl acetate layer was thenwashed with water and was dried over anhydrous sodium sulfate. Thesolvent was removed by distillation under the reduced pressure, and theresidue was purified by column chromatography using acetone-hexane togive[2-(6,7-dimethoxy-quinolin-4-yloxy)-5-methoxy-phenyl]-thiazol-2-yl-methanol(90 mg, yield 52%).

[2-(6,7-Dimethoxy-quinolin-4-yloxy)-5-methoxy-phenyl]-thiazol-2-yl-methanol(90 mg) was dissolved in methanol/methylene chloride (3 ml/9 ml) toprepare a solution, manganese dioxide (90 mg) was added to the solution,and the mixture was stirred at room temperature overnight. The reactionsolution was filtered through Celite, water was added to the filtrate,and the mixture was extracted with ethyl acetate. The solvent wasremoved by distillation under the reduced pressure, and the residue waspurified by column chromatography using acetone-hexane to give the titlecompound (65 mg, yield 74%).

¹H-NMR (CDCl₃, 400 MHz): δ 3.90 (s, 3H), 3.95 (s, 3H), 4.01 (s, 3H),6.53 (d, J=5.4 Hz, 1H), 7.14-7.28 (m, 3H), 7.34 (s, 1H), 7.39 (d, J=2.9Hz, 1H), 7.56 (d, J=3.2 Hz, 1H), 7.87 (d, J=3.2 Hz, 1H), 8.44 (d, J=5.4Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 423 (M+1)⁺

Compound 193{1-[2-(6,7-Dimethoxy-quinolin-4-yloxy)-4,5-dimethylphenyl]-ethylidene}-hydrazine

1-[2-(6,7-Dimethoxy-quinolin-4-yloxy)-4,5-dimethylphenyl]-1-ethanone(compound 38) (50 mg) was dissolved in ethanol (1.5 ml) to prepare asolution. Hydrazine monohydrate (20 mg) and triethylamine (45 mg) wereadded to the solution, and the mixture was stirred under reflux for 3hr. The solvent was removed by distillation under the reduced pressure,water was added to the residue, and the mixture was extracted with ethylacetate. The ethyl acetate layer was then washed with water and wasdried over anhydrous sodium sulfate. The solvent was removed bydistillation under the reduced pressure. The residue was purified bythin layer chromatography using hexane-acetone to give the titlecompound (36 mg, yield 67%).

¹H-NMR (CDCl₃, 400 MHz): δ 1.96 (s, 3H), 2.27 (s, 3H), 2.31 (s, 3H),4.05 (s, 3H), 4.06 (s, 3H), 5.17 (brs, 2H), 6.38 (d, J=5.4 Hz, 1H), 6.91(s, 1H), 7.37 (s, 1H), 7.45 (s, 1H), 7.56 (s, 1H), 8.44 (d, J=5.4 Hz,1H)

Mass spectrometric value (ESI−MS, m/z): 388 (M+Na)⁺

Compound 194N-{1-[2-(6,7-Dimethoxy-quinolin-4-yloxy)-4,5-dimethyl-phenyl]-ethylidene}-N′-pyridin-2-yl-hydrazine

1-[2-(6,7-Dimethoxy-quinolin-4-yloxy)-4,5-dimethylphenyl]-1-ethanone(compound 38) (30 mg) was dissolved in ethanol (1 ml) to prepare asolution. (2-Pyridyl)-hydrazine (28 mg) was added to the solution, andthe mixture was stirred at 60° C. overnight. Ytterbium triflate (1 mg)was added to the reaction solution, and the mixture was stirred at 60°C. for 5 days. The reaction solution was cooled to room temperature,water was then added to the cooled solution, and the mixture wasextracted with ethyl acetate. The ethyl acetate layer was then washedwith water and was dried over anhydrous sodium sulfate. The solvent wasremoved by distillation under the reduced pressure. The residue waspurified by thin layer chromatography using hexane-acetone to give thetitle compound (13 mg, yield 39%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.08-2.16 (m, 3H), 2.28-2.59 (m, 6H),3.99-4.07 (m, 6H), 6.38-6.40 (m, 1H), 6.67-6.75 (m, 1H), 6.92-7.57 (m,6H), 8.01-8.09 (m, 2H), 8.41-8.49 (m, 1H)

Mass spectrometric value (ESI−MS, m/z): 465 (M+Na)⁺

Compound 1951-[2-(6,7-Dimethoxy-quinolin-4-yloxy)-4,5-dimethyl-phenyl]-ethanoneoxime

1-[2-(6,7-Dimethoxy-quinolin-4-yloxy)-4,5-dimethylphenyl]-1-ethanone(compound 38) (30 mg) was dissolved in ethanol (1 ml) to prepare asolution. Hydroxylamine hydrochloride (12 mg) and triethylamine (27 mg)were added to the solution, and the mixture was stirred at roomtemperature overnight. Further, hydroxylamine hydrochloride (12 mg) andtriethylamine (27 mg) were then added to the reaction solution, and themixture was stirred at room temperature for 5 hr. The solvent wasremoved by distillation under the reduced pressure, water was added tothe residue, and the mixture was extracted with ethyl acetate. The ethylacetate layer was then washed with water and was dried over anhydroussodium sulfate. The solvent was removed by distillation under thereduced pressure, and the residue was purified by thin layerchromatography using hexane-acetone to give the title compound (10 mg,yield 31%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.13 (s, 3H), 2.28 (s, 3H), 2.31 (s, 3H),4.02 (s, 3H), 4.03 (s, 3H), 6.37 (d, J=5.4 Hz, 1H), 6.93 (s, 1H), 7.31(s, 1H), 7.41 (s, 1H), 7.52 (s, 1H), 8.39 (d, J=5.4 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 389 (M+Na)⁺

Compound 1961-[2-(6,7-Dimethoxy-quinolin-4-yloxy)-4,5-dimethyl-phenyl]-ethanoneo-methyl-oxime

1-[2-(6,7-Dimethoxy-quinolin-4-yloxy)-4,5-dimethylphenyl]-1-ethanone(compound 38) (30 mg) was dissolved in ethanol (1 ml) to prepare asolution. Methoxyamine hydrochloride (22 mg) and triethylamine (27 mg)were added to the solution, and the mixture was stirred at roomtemperature for 4 hr. The solvent was removed by distillation under thereduced pressure, and the residue was purified by column chromatographyusing hexane-acetone to give the title compound (33 mg, yield 98%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.05 (s, 3H), 2.27 (s, 3H), 2.31 (s, 3H),3.79 (s, 3H), 4.04 (s, 3H), 4.07 (s, 3H), 6.38 (d, J=5.1 Hz, 1H), 6.93(s, 1H), 7.32 (s, 1H), 7.41 (s, 1H), 7.54 (s, 1H), 8.45 (d, J=5.4 Hz,1H)

Mass spectrometric value (ESI−MS, m/z): 403 (M+Na)⁺

Compound 1971-[2-(6,7-Dimethoxy-quinolin-4-yloxy)-4,5-dimethyl-phenyl]-ethanoneo-allyl-oxime

1-[2-(6,7-Dimethoxy-quinolin-4-yloxy)-4,5-dimethylphenyl]-1-ethanone(compound 38) (30 mg) was dissolved in ethanol (1 ml) to prepare asolution. Allyloxyamine hydrochloride (29 mg) and triethylamine (27 mg)were added to the solution, and the mixture was stirred at roomtemperature for 4 hr. The solvent was removed by distillation under thereduced pressure, and the residue was purified by column chromatographyusing hexane-acetone to give the title compound (32 mg, yield 88%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.10 (s, 3H), 2.27 (s, 3H), 2.31 (s, 3H),4.04 (s, 3H), 4.05 (s, 3H), 4.50 (ddd, J=1.4, 1.4, 5.6 Hz, 2H),5.04-5.16 (m, 2H), 5.79-5.91 (m, 1H), 6.38 (d, J=5.1 Hz, 1H), 6.93 (s,1H), 7.31 (s, 1H), 7.41 (s, 1H), 7.54 (s, 1H), 8.45 (d, J=5.1 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 407 (M+1)⁺

Compound 1981-[2-(6,7-Dimethoxy-quinolin-4-yloxy)-4,5-dimethyl-phenyl]-ethanoneo-benzyl-oxime

1-[2-(6,7-Dimethoxy-quinolin-4-yloxy)-4,5-dimethylphenyl]-1-ethanone(compound 38) (30 mg) was dissolved in ethanol (1 ml) to prepare asolution. Benzyloxyamine hydrochloride (43 mg) and triethylamine (27 mg)were added to the solution, and the mixture was stirred at roomtemperature for 4 hr. The mixture was then stirred at 50° C. for 3 days.The reaction solution was cooled to room temperature, the solvent wasthen removed by distillation under the reduced pressure, and the residuewas purified by thin layer chromatography using hexane-acetone to givethe title compound (38 mg, yield 94%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.15 (s, 3H), 2.30 (s, 3H), 2.33 (s, 3H),4.04 (s, 3H), 4.08 (s, 3H), 5.07 (s, 2H), 6.39 (d, J=5.4 Hz, 1H), 6.95(s, 1H), 7.19-7.31 (m, 5H), 7.33 (s, 1H), 7.45 (s, 1H), 7.55 (s, 1H),8.46 (d, J=5.4 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 457 (M+1)⁺

Compound 1991-[2-(6,7-Dimethoxy-quinolin-4-yloxy)-4,5-dimethyl-phenyl]-ethanoneo-phenyl-oxime

1-[2-(6,7-Dimethoxy-quinolin-4-yloxy)-4,5-dimethylphenyl]-1-ethanone(compound 38) (30 mg) was dissolved in ethanol (1 ml) to prepare asolution. Phenoxyamine hydrochloride (39 mg) and triethylamine (27 mg)were added to the solution, and the mixture was stirred at roomtemperature for 4 hr. The reaction solution was then stirred at 50° C.for 3 days. The reaction solution was cooled to room temperature, andthe solvent was then removed by distillation under the reduced pressure.The residue was purified by thin layer chromatography usinghexane-acetone to give the title compound (10 mg, yield 26%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.30 (s, 6H), 2.34 (s, 3H), 3.99 (s, 3H),4.04 (s, 3H), 6.45 (d, J=5.1 Hz, 1H), 6.96 (t, J=7.3 Hz, 1H), 6.97 (s,1H), 7.03 (s, 1H), 7.05 (s, 1H), 7.20 (dd, J=8.8, 8.8 Hz, 2H), 7.42 (d,J=4.4 Hz, 2H), 7.53 (s, 1H), 8.46 (d, J=5.4 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 443 (M+1)⁺

Compound 2001-[3-(6,7-Dimethoxy-quinolin-4-yloxy)-naphthalen-2-yl]-ethanone

Dichloromethane (304 ml) and thionyl chloride (76 ml) were added to3-hydroxynaphthalene-2-carboxylic acid (5 g), and the mixture wasstirred under reflux for 4 hr. The solvent was then removed bydistillation under the reduced pressure. Dioxane (200 ml) was added tothe residue to prepare a solution. A solution ofO,N-dimethylhydroxylamine hydrochloride (7.8 g) in a 2 N aqueous sodiumhydroxide solution was added thereto, and the mixture was stirred atroom temperature for one hr. Under ice cooling, the reaction solutionwas acidified by the addition of 4 N hydrochloric acid, and the mixturewas extracted with ethyl acetate. The ethyl acetate layer was thenwashed with an aqueous potassium carbonate solution and water and wasdried over anhydrous sodium sulfate. The solvent was removed bydistillation under the reduced pressure to give3-hydroxynaphthalene-2-carboxylic acid methoxymethylamide (660 mg, yield11%).

3-Hydroxynaphthalene-2-carboxylic acid methoxymethylamide (600 mg) wasdissolved in tetrahydrofuran (36 ml) to prepare a solution. A solution(9.8 ml) of 0.93 M methylmagnesium bromide in tetrahydrofuran was addedthereto at −78° C., temperature of the mixture was raised to roomtemperature, and the mixture was stirred for 1.5 hr. A saturated aqueousammonium chloride solution was added to stop the reaction, water wasadded thereto, and the mixture was extracted with ethyl acetate. Theethyl acetate layer was then washed with an aqueous potassium carbonatesolution, was washed with water and was dried over anhydrous sodiumsulfate. The solvent was removed by distillation under the reducedpressure, and the residue was purified by column chromatography usinghexane-ethyl acetate to give 1-(3-hydroxynaphthalen-2-yl)-ethanone (378mg, yield 78%).

1-(3-Hydroxynaphthalen-2-yl)-ethanone (249 mg),4-chloro-6,7-dimethoxyquinoline (100 mg), and4-(N,N-dimethylamino)-pyridine (164 mg) were dissolved in1,2-dichlorobenzene (5 ml) to prepare a solution which was then stirredat 130° C. overnight. The reaction solution was cooled to roomtemperature, and the solvent was then removed by distillation under thereduced pressure. Water was added to the residue, and the mixture wasextracted with ethyl acetate. The ethyl acetate layer was then washedwith water and was dried over anhydrous sodium sulfate. The solvent wasremoved by distillation under the reduced pressure. The residue waspurified by thin layer chromatography using hexane-acetone to give thetitle compound (27 mg, yield 16%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.60 (s, 3H), 4.05 (s, 3H), 4.06 (s, 3H),6.46 (d, J=5.2 Hz, 1H), 7.46 (s, 1H), 7.51-7.62 (m, 4H), 7.77 (d, J=8Hz, 1H), 7.99 (d, J=7.6 Hz, 1H), 8.44 (s, 1H), 8.49 (d, J=5.6 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 374 (M+1)⁺

Compound 201 Propyl3-(6,7-dimethoxy-quinolin-4-yloxy)-naphthalene-2-carboxylate

2-Hydroxy-naphthalene-3-carboxylic acid (2 g) was dissolved in1-propanol (10 ml) to prepare a solution. The solution was brought to 0°C., and thionyl chloride (1.16 ml) was gradually added dropwise. Themixture was stirred at 120° C. for 2 hr. The reaction solution wascooled to room temperature, and the solvent was removed by distillationunder the reduced pressure. Water was then added to the residue, and themixture was extracted with chloroform. The chloroform layer was washedwith saturated brine and was dried over anhydrous sodium sulfate. Thesolvent was removed by distillation under the reduced pressure, and theresidue was purified by column chromatography using chloroform to givepropyl 2-hydroxy-3-naphthoate (2.15 g, yield 88%).

Propyl 2-hydroxy-3-naphthoate (400 mg), 4-chloro-6,7-dimethoxyquinoline(130 mg), and 4-dimethylaminopyridine (213 mg) were suspended ino-dichlorobenzene (4 ml), and the suspension was stirred at 140° C. for12.5 hr. The reaction solution was cooled to room temperature, water wasthen added thereto, and the mixture was extracted with chloroform. Thechloroform layer was washed with saturated brine and was dried overanhydrous sodium sulfate. The solvent was removed by distillation underthe reduced pressure, and the residue was purified by thin layerchromatography using chloroform-acetone to give the title compound (108mg, yield 44%).

¹H-NMR (CDCl₃, 400 MHz): δ 0.71 (t, J=7.6 Hz, 3H), 1.29-1.38 (m, 2H),4.03 (t, J=6.8 Hz, 2H), 4.08 (s, 3H), 4.08 (s, 3H), 6.35 (d, J=5.4 Hz,1H), 7.53 (s, 1H), 7.57-7.68 (m, 4H), 7.84 (d, J=8.3 Hz, 1H), 8.02 (d,J=8.3 Hz, 1H), 8.44 (d, J=5.4 Hz, 1H), 8.67 (s, 1H)

Mass spectrometric value (ESI−MS, m/z): 418 (M+1)⁺

Compound 202 6,7-Dimethoxy-4-(2-methyl-pyridin-3-yloxy)-quinoline

4-Chloro-6,7-dimethoxyquinoline (245 mg), 2-methyl-3-pyridinol (227 mg),and 4-dimethylaminopyridine (420 mg) were suspended in o-dichlorobenzene(13 ml), and the suspension was stirred at 135° C. for 2 days. Thereaction solution was cooled to room temperature. The solvent was thenremoved by distillation under the reduced pressure. The residue waspurified by column chromatography using acetone-chloroform to give thetitle compound (324 mg, yield 100%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.48 (s, 3H), 4.07 (s, 3H), 4.07 (s, 3H),6.28 (d, J=5.4 Hz, 1H), 7.27 (m, 1H), 7.42-7.46 (m, 2H), 7.56 (d, J=1.7Hz, 1H), 8.48-8.50 (m, 2H)

Mass spectrometric value (ESI−MS, m/z): 297 (M+1)⁺

Compound 203 4-(2-Bromo-pyridin-3-yloxy)-6,7-dimethoxyquinoline

4-Chloro-6,7-dimethoxyquinoline (226 mg), 2-bromo-3-pyridinol (250 mg),and 4-dimethylaminopyridine (400 mg) were suspended in o-dichlorobenzene(10 ml), and the suspension was stirred at 140° C. for 2 hr. Thereaction solution was cooled to room temperature, the solvent was thenremoved by distillation under the reduced pressure, and the residue waspurified by column chromatography using acetone-chloroform to give thetitle compound (21 mg, yield 6%).

¹H-NMR (CDCl₃, 400 MHz): δ 4.06 (s, 3H), 4.06 (s, 3H), 6.38 (d, J=5.4Hz, 1H), 7.39 (dd, J=4.6, 7.8 Hz, 1H), 7.46 (s, 1H), 7.53 (dd, J=1.7,8.1 Hz, 1H), 7.54 (s, 1H), 8.37 (dd, J=1.6, 4.6 Hz, 1H), 8.54 (d, J=5.1Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 361 (M+1)⁺

Compound 2044-(2-Cyclopentyloxy-pyridin-3-yloxy)-6,7-dimethoxy-quinoline

4-Chloro-6,7-dimethoxyquinoline (252 mg), 2,3-dihydroxypyridine (396mg), and 4-dimethylaminopyridine (400 mg) were suspended ino-dichlorobenzene (13 ml), and the suspension was stirred at 160° C.overnight. The reaction solution was cooled to room temperature, thesolvent was then removed by distillation under the reduced pressure, andthe residue was purified by column chromatography usingacetone-chloroform to give6,7-dimethoxy-4-(2-hydroxy-pyridin-3-yloxy)-quinoline (84 mg, yield25%).

6,7-Dimethoxy-4-(2-hydroxy-pyridin-3-yloxy)-quinoline (21 mg) wasdissolved in chloroform (7 ml) to prepare a solution. Potassiumcarbonate (300 mg) and cyclopentyl bromide (0.2 ml) were added to thesolution. The mixture was stirred at room temperature overnight, waterwas added to the reaction solution, and the mixture was extracted withethyl acetate. The organic layer was washed with water and was driedover anhydrous sodium sulfate. The solvent was removed by distillationunder the reduced pressure, and the residue was purified by columnchromatography using acetone-chloroform to give the title compound (14mg, yield 55%).

¹H-NMR (CDCl₃, 400 MHz): δ 1.23-1.81 (m, 8H), 4.06 (s, 3H), 4.06 (s,3H), 5.43 (m, 1H), 6.31 (d, J=5.1 Hz, 1H), 6.95 (dd, J=1.1, 7.6 Hz, 1H),7.43 (s, 1H), 7.49 (m, 1H), 7.58 (s, 1H), 8.10 (m, 1H), 8.46 (d, J=5.1Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 367 (M+1)⁺

Compound 205 4-(6-Fluoro-pyridin-3-yloxy)-6,7-dimethoxy-quinoline

6-Fluoro-3-hydroxypyridine (10 mg), 4-chloro-6,7-dimethoxyquinoline (59mg), and 4-dimethylaminopyridine (32 mg) were suspended ino-dichlorobenzene (2 ml), and the suspension was stirred at 140° C. for3.5 hr. The reaction solution was cooled to room temperature, water wasthen added to the reaction solution, and the mixture was extracted withethyl acetate. The ethyl acetate layer was then washed with water andsaturated brine and was dried over anhydrous sodium sulfate. The solventwas removed by distillation under the reduced pressure, and the residuewas purified by thin layer chromatography using acetone-chloroform togive the title compound (20 mg, yield 76%).

¹H-NMR (CDCl₃, 400 MHz): δ 3.98 (s, 6H), 6.35 (d, J=5.2 Hz, 1H), 6.99(dd, J=8.8 Hz, 3.6 Hz, 1H), 7.36 (s, 1H), 7.44 (s, 1H), 7.56 (m, 1H),8.09 (s, 1H), 8.46 (d, J=5.2 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 301 (M+1)⁺

Compound 206 4-(6-Chloro-pyridin-3-yloxy)-6,7-dimethoxy-quinoline

2-Chloro-5-hydroxypyridine (100 mg), 4-chloro-6,7-dimethoxyquinoline(861 mg), and 4-dimethylaminopyridine (283 mg) were suspended ino-dichlorobenzene (5 ml), and the suspension was stirred at 140° C. for2 hr. The reaction solution was cooled to room temperature, water wasthen added to the reaction solution, and the mixture was extracted withethyl acetate. The ethyl acetate layer was then washed with water andsaturated brine and was dried over anhydrous magnesium sulfate. Thesolvent was removed by distillation under the reduced pressure, and theresidue was purified by column chromatography using acetone-hexane togive the title compound (164 mg, yield 67%).

¹H-NMR (CDCl₃, 400 MHz): δ 4.00 (s, 3H), 4.02 (s, 3H), 6.45 (d, J=5.2Hz, 1H), 7.31-7.49 (m, 4H), 8.31 (d, J=3.2 Hz, 1H), 8.51 (d, J=5.2 Hz,1H)

Mass spectrometric value (ESI−MS, m/z): 317 (M+1)⁺

Compound 207 6,7-Dimethoxy-4-(6-methoxy-pyridin-3-yloxy)-quinoline

4-(6-Chloro-pyridin-3-yloxy)-6,7-dimethoxy-quinoline (compound 206) (145mg) and sodium methoxide (87 mg) were suspended in toluene (1.2 ml), andthe suspension was heated under reflux for 20 hr. The reaction solutionwas cooled to room temperature, water was then added to the reactionsolution, and the mixture was extracted with chloroform. The chloroformlayer was then washed with water and saturated brine and was dried overanhydrous magnesium sulfate. The solvent was removed by distillationunder the reduced pressure, and the residue was purified by thin layerchromatography using acetone-hexane to give the title compound (88 mg,yield 61%).

¹H-NMR (CDCl₃, 400 MHz): δ 3.89 (s, 3H), 3.96 (s, 3H), 3.97 (s, 3H),6.31 (d, J=5.2 Hz, 1H), 6.76 (d, J=9.2 Hz, 1H), 7.31-7.39 (m, 2H), 7.47(s, 1H), 8.02 (d, J=2.8 Hz, 1H), 8.41 (d, J=5.2 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 313 (M+1)⁺

Compound 208 4-(5-Chloro-pyridin-3-yloxy)-6,7-dimethoxy-quinoline

4-Chloro-6,7-dimethoxyquinoline (245 mg), 3-chloro-5-pyridinol (277 mg),and 4-dimethylaminopyridine (377 mg) were suspended in o-dichlorobenzene(13 ml), and the mixture was stirred at 140° C. for 6 hr. Water wasadded to the reaction solution, and the mixture was extracted with ethylacetate. The organic layer was washed with an aqueous sodium hydroxidesolution and water and was dried over anhydrous sodium sulfate. Thesolvent was removed by distillation under the reduced pressure, and theresidue was purified by column chromatography using acetone-chloroformto give the title compound (283 mg, yield 81%).

¹H-NMR (CDCl₃, 400 MHz): δ 4.04 (s, 3H), 4.06 (s, 3H), 6.56 (d, J=5.1Hz, 1H), 7.44 (s, 1H), 7.46 (s, 1H), 7.53 (m, 1H), 8.47 (d, J=2.4 Hz,1H), 8.51 (d, J=1.9 Hz, 1H), 8.58 (d, J=5.1 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 317 (M+1)⁺

Compound 209 4-(2,6-Dimethyl-pyridin-3-yloxy)-6,7-dimethoxy-quinoline

2,6-Dimethylpyridin-3-ol (165 mg), 4-chloro-6,7-dimethoxyquinoline (100mg), and 4-(N,N-dimethylamino)-pyridine (164 mg) were dissolved in1,2-dichlorobenzene (4.5 ml) to prepare a solution which was thenstirred at 130° C. overnight. The reaction solution was cooled to roomtemperature, and the solvent was then removed by distillation under thereduced pressure. Water was added to the residue, the mixture wasextracted with ethyl acetate, and the ethyl acetate layer was thenwashed with water and was dried over anhydrous sodium sulfate. Thesolvent was removed by distillation under the reduced pressure, and theresidue was purified by column chromatography using hexane-acetone togive the title compound (116 mg, yield 83%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.41 (s, 3H), 2.60 (s, 3H), 4.08 (s, 6H),6.30 (d, J=5.6 Hz, 1H), 7.12 (d, J=8.3 Hz, 1H), 7.33 (d, J=8.3 Hz, 1H),7.56 (s, 1H), 7.59 (s, 1H), 8.47 (d, J=5.6 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 311 (M+1)⁺

Compound 2106,7-Dimethoxy-4-(6-methyl-2-nitro-pyridin-3-yloxy)-quinoline

2-Nitro-6-methylpyridin-3-ol (4.1 g), 4-chloro-6,7-dimethoxyquinoline (2g), and 4-(N,N-dimethylamino)-pyridine (3.3 g) were dissolved in1,2-dichlorobenzene (90 ml) to prepare a solution which was then stirredat 130° C. overnight. The reaction solution was cooled to roomtemperature, and the solvent was then removed by distillation under thereduced pressure. A 1 N aqueous sodium hydroxide solution was added tothe residue, the mixture was extracted with ethyl acetate, and the ethylacetate layer was then washed with water and was dried over anhydroussodium sulfate. The solvent was removed by distillation under thereduced pressure, and the residue was purified by column chromatographyusing hexane-acetone to give the title compound (732 mg, yield 24%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.67 (s, 3H), 4.02 (s, 3H), 4.05 (s, 3H),6.52 (d, J=5.4 Hz, 1H), 7.43 (s, 1H), 7.44 (s, 1H), 7.49 (d, J=8.5 Hz,1H), 7.59 (d, J=8.5 Hz, 1H), 8.56 (d, J=5.1 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 364 (M+Na)⁺

Compound 211 4-(6-Fluoro-2-iodo-pyridin-3-yloxy)-6,7-dimethoxy-quinoline

6-Fluoro-3-hydroxypyridine (870 mg) and iodine (9.76 g) were dissolvedin a mixed solvent composed of methanol (20 ml) and water (10 ml) toprepare a solution which was then stirred at room temperature for 120hr. Thereafter, sodium sulfite was added until the solution becametransparent. Methanol in the reaction solution was removed under thereduced pressure, water was added to the residue, and the mixture wasextracted with chloroform. The chloroform layer was washed with waterand saturated brine and was dried over anhydrous magnesium sulfate. Thesolvent was removed by distillation under the reduced pressure, and theresidue was purified by column chromatography using acetone-chloroformto give 6-fluoro-2-iodo-pyridin-3-ol (350 mg, yield 19%).

6-Fluoro-2-iodo-pyridin-3-ol (20 mg), 4-chloro-6,7-dimethoxyquinoline(56 mg), and 4-dimethylaminopyridine (31 mg) were suspended ino-dichlorobenzene (2 ml), and the suspension was stirred at 140° C. for5 hr. The reaction solution was cooled to room temperature, water wasthen added to the reaction solution, and the mixture was extracted withethyl acetate. The ethyl acetate layer was then washed with water andsaturated brine and was dried over anhydrous magnesium sulfate. Thesolvent was removed by distillation under the reduced pressure, and theresidue was purified by thin layer chromatography usingacetone-chloroform to give the title compound (2 mg, yield 6%).

¹H-NMR (CDCl₃, 400 MHz): δ 3.99 (s, 3H), 4.00 (s, 3H), 6.27 (d, J=5.6Hz, 1H), 6.95 (dd, J=8.4 Hz, 3.6 Hz, 1H), 7.37-7.50 (m, 3H), 8.47 (d,J=5.2 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 875 (2M+Na)⁺

Compound 2126,7-Dimethoxy-4-(6-methyl-2-trimethylsilanylethynyl-pyridin-3-yloxy)-quinoline

4-[(2-Iodo-6-methyl-3-pyridyl)oxy]-6,7-dimethoxy-quinoline (compound116) (84 mg), trimethylsilylacetylene (39 mg), andbis(triphenylphosphine)palladium(II) chloride (14 mg) were dissolved intetrahydrofuran (1 ml) to prepare a solution. Diisopropylethylamine (0.2ml) and copper iodide (3.8 mg) were added to the solution, and themixture was stirred at room temperature for 18 hr. The reaction solutionwas filtered, the solvent was then removed by distillation under thereduced pressure, and the residue was purified by column chromatographyusing chloroform to give the title compound (45 mg, yield 58%).

¹H-NMR (CDCl₃, 400 MHz): δ −0.17 (s, 9H), 2.62 (s, 3H), 4.06 (s, 3H),4.06 (s, 3H), 6.33 (d, J=5.6 Hz, 1H), 7.24 (d, J=8.4 Hz, 1H), 7.48 (d,J=8.4 Hz, 1H), 7.50 (s, 1H), 7.60 (s, 1H), 8.51 (d, J=5.2 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 393 (M+1)⁺

Compound 2133-(6,7-Dimethoxy-quinolin-4-yloxy)-6-methyl-pyridin-2-carbonitrile

2-Hydroxymethyl-6-methyl-pyridin-3-ol (1.03 g) was suspended indichloromethane (50 ml), manganese dioxide (5.53 g) was added to thesuspension, and the mixture was stirred at room temperature for 3 days.The reaction solution was filtered, and the solvent was removed bydistillation under the reduced pressure. The residue was used in thenext reaction without purification.

The residue was dissolved in N,N-dimethylformamide (40 ml) to prepare asolution. Potassium carbonate (2.35 g) and benzyl chloride (0.8 ml) wereadded to the solution, and the mixture was stirred at room temperatureovernight. Water was added to the reaction solution, and the mixture wasextracted with ethyl acetate. The organic layer was washed with waterand was dried over anhydrous sodium sulfate. The solvent was removed bydistillation under the reduced pressure, and the residue was purified bycolumn chromatography using ethyl acetate-hexane to give3-benzyloxy-6-methyl-pyridine-2-carbaldehyde (881 mg, yield 52%) (2steps).

3-Benzyloxy-6-methyl-pyridine-2-carbaldehyde (100 mg) was dissolved inacetonitrile (5 ml) to prepare a solution. Hydroxylamine hydrochloride(72 mg) and triethylamine (0.25 ml) were added to the solution, and themixture was stirred at room temperature for one hr. 4-Nitrophthalicanhydride was added to the reaction solution, and the mixture wasstirred at 100° C. overnight. Water was added to the reaction solution,and the mixture was extracted with ethyl acetate. The organic layer waswashed with water and was dried over anhydrous sodium sulfate. Thesolvent was removed by distillation under the reduced pressure, and theresidue was purified by column chromatography using ethyl acetate-hexaneto give 3-benzyloxy-6-methylpyridine-2-carbonitrile (53 mg, yield 54%).

Trifluoroacetic acid (1.5 ml) and methanesulfonic acid (0.15 ml) wereadded to 3-benzyloxy-6-methylpyridine-2-carbonitrile (50 mg) to preparea solution which was then stirred at room temperature for one hr. Thesolvent was removed by distillation under the reduced pressure, waterwas then added to the reaction solution, and the mixture was extractedwith ethyl acetate. The organic layer was washed with an aqueous sodiumhydrogencarbonate solution and water and was dried over anhydrous sodiumsulfate. The solvent was removed by distillation under the reducedpressure, and the residue was used in the next reaction withoutpurification.

The residue, 4-chloro-6,7-dimethoxyquinoline (94 mg), and4-dimethylaminopyridine (90 mg) were suspended in o-dichlorobenzene (4ml), and the suspension was stirred at 140° C. for 6 hr. The reactionsolution was cooled to room temperature, and the solvent was thenremoved by distillation under the reduced pressure. The residue waspurified by column chromatography using acetone-chloroform to give thetitle compound (12 mg, yield 17%) (2 steps).

¹H-NMR (CDCl₃, 400 MHz): δ 2.65 (s, 3H), 4.05 (s, 3H), 4.06 (s, 3H),6.54 (d, J=5.1 Hz, 1H), 7.41 (d, J=8.8 Hz, 1H), 7.44 (d, J=8.8 Hz, 1H),7.46 (s, 1H), 7.46 (s, 1H), 8.59 (d, J=5.1 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 344 (M+Na)⁺

Compound 2144-(2-Benzyl-6-methyl-pyridin-3-yloxy)-6,7-dimethoxy-quinoline

[3-(6,7-Dimethoxy-quinolin-4-yloxy)-6-methyl-pyridin-2-yl]-phenyl methylacetate (compound 218) (40 mg) was dissolved in N,N-dimethylformamide (5ml) to prepare a solution. Triethylamine (0.3 ml) and 20% palladiumhydroxide (10 mg) were added to the solution, and the mixture wasstirred under hydrogen pressure at room temperature overnight. Thereaction solution was filtered through Celite and was then washed withchloroform and methanol. The solvent was removed by distillation underthe reduced pressure, and the residue was purified by thin layerchromatography using chloroform-acetone to give the title compound (32mg, yield 92%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.64 (s, 3H), 3.96 (s, 3H), 4.07 (s, 3H),4.10 (s, 2H), 6.19 (d, J=5.6 Hz, 1H), 7.10-7.15 (m, 6H), 7.30 (d, J=8.3Hz, 1H), 7.36 (s, 1H), 7.51 (s, 1H), 8.38 (d, J=5.4 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 387 (M+1)⁺

Compound 2156,7-Dimethoxy-4-[6-methyl-2-(6-methyl-pyridin-2-ylmethyl)-pyridin-3-yloxy]-quinoline

3-(6,7-Dimethoxy-quinolin-4-yloxy)-6-methyl-pyridin-2-yl]-(6-methyl-pyridin-2-yl)-methylacetate (compound 219) (25 mg) was dissolved in N,N-dimethylformamide (1ml) to prepare a solution. Triethylamine (0.2 ml) and 20% palladiumhydroxide (14 mg) were added to the solution, and the mixture wasstirred under hydrogen pressure at room temperature overnight. Thereaction solution was filtered through Celite and was then washed withchloroform and methanol. The solvent was removed by distillation underthe reduced pressure, and the residue was purified by thin layerchromatography using chloroform-acetone to give the title compound (13mg, yield 59%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.23 (s, 3H), 2.64 (s, 3H), 3.97 (s, 3H),4.04 (s, 3H), 4.33 (s, 2H), 6.15 (d, J=5.4 Hz, 1H), 6.80 (d, J=7.6 Hz,1H), 6.85 (d, J=7.8 Hz, 1H), 7.16 (d, J=8.1 Hz, 1H), 7.28-7.34 (m, 3H),7.40 (s, 1H), 8.34 (d, J=5.1 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 402 (M+1)⁺

Compound 2166,7-Dimethoxy-4-(6-methyl-2-styryl-pyridin-3-yloxy)-quinoline

4-[(2-Iodo-6-methyl-3-pyridyl)oxy]-6,7-dimethoxy-quinoline (compound116) (84 mg), trans-2-phenylvinylboronic acid (148 mg), andtetrakistriphenylphosphine palladium (12 mg) were dissolved in toluene(1 ml) to prepare a solution. A saturated aqueous sodiumhydrogencarbonate solution (1 ml) was added to the solution, and themixture was stirred at 80° C. for 3 hr. The reaction solution wasfiltered, and the solvent was then removed by distillation under thereduced pressure. The residue was purified by column chromatographyusing methanol-chloroform to give the title compound (53 mg, yield 67%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.64 (s, 3H), 4.05 (s, 3H), 4.06 (s, 3H),6.33 (d, J=5.4 Hz, 1H), 7.10 (d, J=8.3 Hz, 1H), 7.18-7.26 (m, 4H), 7.31(d, J=8.3 Hz, 1H), 7.40 (m, 2H), 7.45 (s, 1H), 7.62 (s, 1H), 7.88 (d,J=15.8 Hz, 1H), 8.45 (d, J=5.4 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 399 (M+1)⁺

Compound 217[3-(6,7-Dimethoxy-quinolin-4-yloxy)-6-methyl-pyridin-2-yl]-phenyl-methanol

[3-(6,7-Dimethoxy-quinolin-4-yloxy)-6-methyl-pyridin-2-yl]-phenyl-methanone(55 mg) (compound 220) was dissolved in methanol (3 ml) to prepare asolution. Sodium borohydride (26 mg) was added to the solution at 0° C.,and the mixture was stirred at room temperature for 2 hr. The solventwas removed by distillation under the reduced pressure, water was addedto the residue, and the mixture was extracted with ethyl acetate. Theethyl acetate layer was then washed with saturated brine and was driedover anhydrous sodium sulfate. The solvent was removed by distillationunder the reduced pressure, and the residue was purified by thin layerchromatography using chloroform-acetone to give the title compound (52mg, yield 92%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.70 (s, 3H), 3.95 (s, 3H), 4.08 (s, 3H),5.74-5.79 (m, 2H), 6.07 (d, J=5.4 Hz, 1H), 7.07-7.31 (m, 8H), 7.52 (s,1H), 8.31 (d, J=5.4 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 403 (M+1)⁺

Compound 218[3-(6,7-Dimethoxy-quinolin-4-yloxy)-6-methyl-pyridin-2-yl]-phenyl-methylacetate

[3-(6,7-Dimethoxy-quinolin-4-yloxy)-6-methyl-pyridin-2-yl]-phenyl-methanol(47 mg) (compound 217) was dissolved in chloroform (7 ml) to prepare asolution. Triethylamine (1 ml), acetic anhydride (0.8 ml), and4-dimethylaminopyridine (20 mg) were added to the solution, and themixture was stirred at room temperature overnight. Water was added tothe reaction solution, and the mixture was extracted with chloroform.The chloroform layer was washed with saturated brine and was dried overanhydrous sodium sulfate, and the solvent was removed by distillationunder the reduced pressure. The residue was purified by thin layerchromatography using chloroform-acetone to give the title compound (48mg, yield 89%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.01 (s, 3H), 2.65 (s, 3H), 3.98 (s, 3H),4.08 (s, 3H), 6.28 (d, J=5.4 Hz, 1H), 6.91 (s, 1H), 7.16-7.35 (m, 7H),7.40 (s, 1H), 7.56 (s, 1H), 8.40 (d, J=5.4 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 445 (M+1)⁺

Compound 219[3-(6,7-Dimethoxy-quinolin-4-yloxy)-6-methyl-pyridin-2-yl]-(6-methyl-pyridin-2-yl)-methylacetate

4-(2-Iodo-6-methyl-pyridin-3-yloxy)-6,7-dimethoxy-quinoline (compound116) (100 mg) was dissolved in tetrahydrofuran (7 ml) to prepare asolution which was then brought to −78° C. n-Butyllithium hexanesolution (0.22 ml) was slowly added dropwise thereto, and the mixturewas stirred at −78° C. for 20 min. 6-Methyl-2-pyridine-carbaldehyde (57mg) was dissolved in tetrahydrofuran (7 ml) to prepare a solution whichwas then added dropwise to the reaction solution, followed by stirringat room temperature for 5 hr. Water was added to the reaction solution,and the mixture was extracted with ethyl acetate. The ethyl acetatelayer was then washed with saturated brine and was dried over anhydroussodium sulfate. The solvent was removed by distillation under thereduced pressure, and the residue was purified by thin layerchromatography using chloroform-acetone to give[3-(6,7-dimethoxy-quinolin-4-yloxy)-6-methyl-pyridin-2-yl]-(6-methyl-pyridin-2-yl)-methanol(73 mg, yield 73%).

[3-(6,7-Dimethoxy-quinolin-4-yloxy)-6-methyl-pyridin-2-yl]-(6-methyl-pyridin-2-yl)-methanol(43 mg) was dissolved in chloroform (6 ml) to prepare a solution.Triethylamine (0.9 ml) and acetic anhydride (0.45 ml) were added to thesolution, and the mixture was stirred at room temperature overnight.Water was added to the reaction solution, and the mixture was extractedwith chloroform. The chloroform layer was washed with saturated brineand was dried over anhydrous sodium sulfate. The solvent was removed bydistillation under the reduced pressure, and the residue was purified bythin layer chromatography using chloroform-acetone to give the titlecompound (28 mg, yield 61%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.10 (s, 3H), 2.27 (s, 3H), 2.62 (s, 3H),4.03 (s, 3H), 4.07 (s, 3H), 6.28 (d, J=5.6 Hz, 1H), 6.91 (d, J=7.6 Hz,1H), 7.07 (s, 1H), 7.16-7.19 (m, 2H), 7.30-7.55 (m, 4H), 8.37 (d, J=5.4Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 460 (M+1)⁺

Compound 220[3-(6,7-Dimethoxy-quinolin-4-yloxy)-6-methyl-pyridin-2-yl]-phenyl-methanone

2,6-Lutidine-α2,3-diol (2.25 g) was dissolved in methanol (15 ml) anddichloromethane (45 ml) to prepare a solution. Manganese dioxide (8.34g) was added to the solution, and the mixture was stirred at roomtemperature overnight. The reaction solution was filtered through Celiteand was then washed with chloroform and methanol. The solvent wasremoved by distillation under the reduced pressure, and the residue waspurified by column chromatography using chloroform-acetone to give3-hydroxy-6-methyl-pyridine-2-carbaldehyde (1.88 g, yield 85%).

3-Hydroxy-6-methyl-pyridine-2-carbaldehyde (350 mg) was dissolved intetrahydrofuran (13 ml) to prepare a solution which was brought to −78°C. Phenylmagnesium bromide (7.4 ml) was slowly added dropwise thereto,and the mixture was stirred at room temperature for one hr. Water wasadded to the reaction solution, and the mixture was extracted with ethylacetate. The ethyl acetate layer was then washed with saturated brineand was dried over anhydrous sodium sulfate. The solvent was removed bydistillation under the reduced pressure, and the residue was purified bythin layer chromatography using chloroform-acetone to give2-(hydroxy-phenyl-methyl)-6-methyl-pyridin-3-ol (553 mg, yield 100%).

2-(Hydroxy-phenyl-methyl)-6-methyl-pyridin-3-ol (553 mg) was dissolvedin methanol (3 ml) and dichloromethane (9 ml) to prepare a solution.Manganese dioxide (2.05 g) was added to the solution, and the mixturewas stirred at room temperature overnight. The reaction solution wasfiltered through Celite and was then washed with chloroform andmethanol. The solvent was removed by distillation under the reducedpressure, and the residue was purified by thin layer chromatographyusing chloroform-acetone to give(3-hydroxy-6-methyl-pyridin-2-yl)-phenyl-methanone (439 mg, yield 80%).

(3-Hydroxy-6-methyl-pyridin-2-yl)-phenyl-methanone (213 mg),4-chloro-6,7-dimethoxyquinoline (223 mg), and 4-dimethylaminopyridine(366 mg) were suspended in o-dichlorobenzene (3 ml), and the suspensionwas stirred at 120° C. overnight. The reaction solution was cooled toroom temperature, water was then added thereto, and the mixture wasextracted with chloroform. The chloroform layer was washed withsaturated brine and was dried over anhydrous sodium sulfate. The solventwas removed by distillation under the reduced pressure, and the residuewas purified by thin layer chromatography using chloroform-acetone togive the title compound (89 mg, yield 22%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.68 (s, 3H), 3.89 (s, 3H), 4.03 (s, 3H),6.52 (d, J=5.4 Hz, 1H), 7.19 (s, 1H), 7.39-7.45 (m, 4H), 7.51-7.55 (m,2H), 7.85 (d, J=7.1 Hz, 2H), 8.47 (d, J=5.6 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 401 (M+1)⁺

Compound 221[3-(6,7-Dimethoxy-quinolin-4-yloxy)-6-methyl-pyridin-2-yl]-(6-methyl-pyridin-2-yl)-methanone

[3-(6,7-Dimethoxy-quinolin-4-yloxy)-6-methyl-pyridin-2-yl]-(6-methyl-pyridin-2-yl)-methanol(20 mg) was dissolved in methanol (0.4 ml) and dichloromethane (1.2 ml)to prepare a solution. Manganese dioxide (300 mg) was added to thesolution, and the mixture was stirred at room temperature for 6 days.The reaction solution was filtered through Celite and was then washedwith chloroform and methanol. The solvent was removed by distillationunder the reduced pressure, and the residue was purified by thin layerchromatography using chloroform-acetone to give the title compound (6mg, yield 28%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.28 (s, 3H), 2.70 (s, 3H), 3.89 (s, 3H),4.01 (s, 3H), 6.77 (d, J=5.4 Hz, 1H), 7.06 (s, 1H), 7.08 (s, 1H),7.35-7.39 (m, 2H), 7.48 (d, J=8.3 Hz, 1H), 7.56 (t, J=7.8 Hz, 1H), 7.82(d, J=7.1 Hz, 1H), 8.50 (d, J=5.4 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 438 (M+Na)⁺

Compound 2224-(5-Chloro-2-cyclopentyloxy-pyridin-3-yloxy)-6,7-dimethoxy-quinoline

4-Chloro-6,7-dimethoxyquinoline (226 mg), 3-chloro-5,6-dihydroxypyridine(290 mg), and 4-dimethylaminopyridine (360 mg) were suspended ino-dichlorobenzene (13 ml), and the suspension was stirred at 160° C. for3 hr. The reaction solution was cooled to room temperature, water wasthen added to the residue, and the mixture was extracted withchloroform. The chloroform layer was washed with water and was driedover anhydrous sodium sulfate. The solvent was removed by distillationunder the reduced pressure, and the residue was purified by columnchromatography using methanol-chloroform to give4-(5-chloro-2-hydroxy-pyridin-3-yloxy)-6,7-dimethoxy-quinoline (83 mg,yield 25%).

4-(5-Chloro-2-hydroxy-pyridin-3-yloxy)-6,7-dimethoxy-quinoline (39 mg)was suspended in N,N-dimethylformamide (7 ml). Cyclopentyl bromide (0.3ml) and potassium carbonate (300 mg) were added to the suspension, andthe mixture was stirred at room temperature for 2 hr. Water was added tothe reaction solution, and the mixture was extracted with ethyl acetate.The organic layer was washed with an aqueous sodium hydrogencarbonatesolution and water and was dried over anhydrous sodium sulfate. Thesolvent was removed by distillation under the reduced pressure, and theresidue was purified by column chromatography using acetone-chloroformto give the title compound (29 mg, yield 62%).

¹H-NMR (CDCl₃, 400 MHz): δ 1.24-1.78 (m, 8H), 4.05 (s, 3H), 4.06 (s,3H), 5.38 (m, 1H), 6.35 (d, J=5.1 Hz, 1H), 7.44 (s, 1H), 7.51 (m, 2H),8.05 (m, 1H), 8.50 (d, J=5.1 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 401 (M+1)⁺

Compound 2236,7-Dimethoxy-4-(6-methyl-2-phenyl-pyridin-3-yloxy)-quinoline

4-[(2-Iodo-6-methyl-3-pyridyl)oxy]-6,7-dimethoxy-quinoline (compound116) (84 mg), phenylboronic acid (121 mg), andtetrakistriphenylphosphine palladium (23 mg) were dissolved in toluene(1 ml) to prepare a solution. A saturated aqueous sodiumhydrogencarbonate solution (0.5 ml) was added to the solution, and themixture was stirred at 80° C. for 3 hr. The reaction solution wasfiltered, the solvent was then removed by distillation under the reducedpressure, and the residue was purified by column chromatography usingmethanol-chloroform to give the title compound (74 mg, yield 100%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.69 (s, 3H), 4.03 (s, 3H), 4.05 (s, 3H),6.39 (d, J=5.4 Hz, 1H), 7.22-7.59 (m, 5H), 7.65-7.70 (m, 2H), 7.81-7.84(m, 2H), 8.42 (dd, J=2.0, 5.6 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 373 (M+1)⁺

Compound 2246,7-Dimethoxy-4-(6-methyl-2-o-tolyl-pyridin-3-yloxy)-quinoline

4-[(2-Iodo-6-methyl-3-pyridyl)oxy]-6,7-dimethoxy-quinoline (compound116) (84 mg), 2-methylphenylboronic acid (136 mg), andtetrakistriphenylphosphine palladium (12 mg) were dissolved in toluene(1 ml) to prepare a solution. A saturated aqueous sodiumhydrogencarbonate solution (1 ml) was added to the solution, and themixture was stirred at 80° C. for 3 hr. The reaction solution wasfiltered, the solvent was then removed by distillation under the reducedpressure, and the residue was purified by column chromatography usingmethanol-chloroform to give the title compound (68 mg, yield 89%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.25 (s, 3H), 2.64 (s, 3H), 3.93 (s, 3H),3.96 (s, 3H), 6.33 (d, J=5.4 Hz, 1H), 6.97-7.70 (m, 4H), 7.20-7.27 (m,2H), 7.29 (s, 1H), 7.47 (d, J=8.3 Hz, 1H), 8.38 (d, J=5.4 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 387 (M+1)⁺

Compound 2251-{2-[3-(6,7-Dimethoxy-quinolin-4-yloxy)-6-methyl-pyridin-2-yl]-phenyl}-ethanone

Toluene (1 ml) and a saturated aqueous sodium hydrogencarbonate solution(0.5 ml) were added to4-(2-iodo-6-methyl-pyridin-3-yloxy)-6,7-dimethoxy-quinoline (compound116) (50 mg), tetrakistriphenylphosphine palladium (14 mg), and2-acetylphenylboronic acid (97 mg) under an argon atmosphere, and themixture was stirred at 80° C. overnight. The reaction solution wascooled to room temperature, a 1 N aqueous sodium hydroxide solution wasthen added, and the mixture was extracted with chloroform. Thechloroform layer was then washed with water and was dried over anhydroussodium sulfate. The solvent was removed by distillation under thereduced pressure, and the residue was purified by thin layerchromatography using chloroform-methanol to give the title compound (10mg, yield 20%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.38 (s, 3H), 2.64 (s, 3H), 4.01 (s, 3H),4.03 (s, 3H), 6.47 (d, J=5.4 Hz, 1H), 7.23 (d, J=8.3 Hz, 1H), 7.32-7.42(m, 5H), 7.52-7.59 (m, 2H), 8.41 (d, J=5.4 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 415 (M+1)⁺

Compound 2262-[3-(6,7-Dimethoxy-quinolin-4-yloxy)-6-methyl-pyridin-2-yl]-phenol

Toluene (1 ml) and a saturated aqueous sodium hydrogencarbonate solution(0.5 ml) were added to4-(2-iodo-6-methyl-pyridin-3-yloxy)-6,7-dimethoxy-quinoline (compound116) (50 mg), tetrakistriphenylphosphine palladium (14 mg), and2-hydroxyphenylboronic acid (81 mg) under an argon atmosphere, and themixture was stirred at 80° C. overnight. The reaction solution wascooled to room temperature, water was then added to the reactionsolution, and the mixture was extracted with chloroform. The chloroformlayer was then washed with water and was dried over anhydrous sodiumsulfate. The solvent was removed by distillation under the reducedpressure, and the residue was purified by thin layer chromatographyusing chloroform-methanol to give the title compound (45 mg, yield 93%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.68 (s, 3H), 4.03 (s, 3H), 4.05 (s, 3H),6.43 (d, J=5.4 Hz, 1H), 6.56 (dd, J=8.0, 8.0 Hz, 1H), 6.86-7.62 (m, 7H),8.07 (d, J=8, 3 Hz, 1H), 8.46 (d, J=5.4 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 389 (M+1)⁺

Compound 2276,7-Dimethoxy-4-[2-(2-methoxy-phenyl)-6-methyl-pyridin-3-yloxy]-quinoline

4-(2-Iodo-6-methyl-pyridin-3-yloxy)-6,7-dimethoxy-quinoline (compound116) (84 mg), 2-methoxyphenylboronic acid (152 mg), andtetrakistriphenylphosphine palladium (12 mg) were dissolved in toluene(1 ml) to prepare a solution. A saturated aqueous sodiumhydrogencarbonate solution (1 ml) was added to the solution, and themixture was stirred at 80° C. for 3 hr. The reaction solution wasfiltered, the solvent was then removed by distillation under the reducedpressure, and the residue was purified by column chromatography usingmethanol-chloroform to give the title compound (23 mg, yield 29%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.65 (s, 3H), 3.32 (s, 3H), 3.87 (s, 3H),3.99 (s, 3H), 6.57 (d, J=5.4 Hz, 1H), 6.67 (d, J=8.3 Hz, 1H), 6.92 (ddd,J=1.0, 7.3, 7.6 Hz, 1H), 7.18-7.26 (m, 3H), 7.35 (dd, J=1.7, 7.6 Hz,1H), 7.36 (s, 1H), 7.46 (d, J=8.3 Hz, 1H), 8.45 (d, J=5.4 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 403 (M+1)⁺

Compound 2284-[2-(2-Chloro-phenyl)-6-methyl-pyridin-3-yloxy]-6,7-dimethoxy-quinoline

Toluene (0.7 ml) and a saturated aqueous sodium hydrogencarbonatesolution (0.35 ml) were added to4-(2-iodo-6-methyl-pyridin-3-yloxy)-6,7-dimethoxy-quinoline (compound116) (50 mg), tetrakistriphenylphosphine palladium (14 mg), and2-chlorophenyl boronic acid (81 mg) under an argon atmosphere, and themixture was stirred at 80° C. for 3 days. The reaction solution wascooled to room temperature, water was then added to the reactionsolution, and the mixture was extracted with ethyl acetate. The ethylacetate layer was then washed with water and was dried over anhydroussodium sulfate. The solvent was removed by distillation under thereduced pressure, and the residue was purified by thin layerchromatography using chloroform-acetone to give the title compound (43mg, yield 90%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.68 (s, 3H), 4.00 (s, 3H), 4.00 (s, 3H),6.41 (d, J=5.4 Hz, 1H), 7.10-7.17 (m, 2H), 7.17-7.29 (m, 4H), 7.44 (s,1H), 7.52 (d, J=5.6 Hz, 1H), 8.42 (d, J=5.1 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 407 (M+1)⁺

Compound 2296,7-Dimethoxy-4-(6-methyl-2-m-tolyl-pyridin-3-yloxy)-quinoline

4-[(2-Iodo-6-methyl-3-pyridyl)oxy]-6,7-dimethoxy-quinoline (compound116) (84 mg), 3-methylphenylboronic acid (136 mg), andtetrakistriphenylphosphine palladium (12 mg) were dissolved in toluene(1 ml) to prepare a solution. A saturated aqueous sodiumhydrogencarbonate solution (1 ml) was added to the solution, and themixture was stirred at 80° C. for 3 hr. The reaction solution wasfiltered, the solvent was then removed by distillation under the reducedpressure, and the residue was purified by column chromatography usingmethanol-chloroform to give the title compound (72 mg, yield 94%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.22 (s, 3H), 2.65 (s, 3H), 4.00 (s, 3H),4.00 (s, 3H), 6.32 (d, J=5.4 Hz, 1H), 7.03 (d, J=7.6 Hz, 1H), 7.11 (m,1H), 7.17 (d, J=8.3 Hz, 1H), 7.36 (s, 1H), 7.41 (d, J=8.3 Hz, 1H), 7.48(s, 1H), 7.58-7.67 (m, 2H), 8.38 (d, J=5.1 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 387 (M+1)⁺

Compound 2306,7-Dimethoxy-4-[6-methyl-2-(3-trifluoromethyl-phenyl)-pyridin-3-yloxy]-quinoline

N,N-Dimethylformamide (1 ml), ethanol (0.5 ml), and a 2 M aqueouspotassium carbonate solution (1 ml) were added to4-(2-iodo-6-methyl-pyridin-3-yloxy)-6,7-dimethoxy-quinoline (compound116) (50 mg), tetrakistriphenylphosphine palladium (14 mg), and3-trifluoromethylphenylboronic acid (67 mg) under an argon atmosphere,and the mixture was stirred at 80° C. for 3 hr. The reaction solutionwas cooled to room temperature, water was then added to the solution,and the mixture was extracted with ethyl acetate. The ethyl acetatelayer was then washed with water and was dried over anhydrous sodiumsulfate, the solvent was removed by distillation under the reducedpressure, and the residue was purified by thin layer chromatographyusing chloroform-acetone to give the title compound (50 mg, yield 95%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.71 (s, 3H), 4.05 (s, 6H), 6.33 (d, J=5.4Hz, 1H), 7.29 (d, J=8.3 Hz, 1H), 7.38-7.60 (m, 5H), 8.04 (d, J=8.3 Hz,1H), 8.23 (s, 1H), 8.40 (d, J=5.1 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 441 (M+1)⁺

Compound 231{3-[3-(6,7-Dimethoxy-quinolin-4-yloxy)-6-methyl-pyridin-2-yl]-phenyl}-methanol

Toluene (1 ml) and a saturated aqueous sodium hydrogencarbonate solution(0.5 ml) were added to4-(2-iodo-6-methyl-pyridin-3-yloxy)-6,7-dimethoxy-quinoline (compound116) (50 mg), tetrakis-triphenylphosphine palladium (14 mg), and(3-hydroxymethyl)-phenylboronic acid (90 mg) under an argon atmosphere,and the mixture was stirred 80° C. overnight. The reaction solution wascooled to room temperature, a 1 N aqueous sodium hydroxide solution wasthen added thereto, and the mixture was extracted with chloroform. Thechloroform layer was then washed with water and was dried over anhydroussodium sulfate. The solvent was removed by distillation under thereduced pressure, and the residue was purified by thin layerchromatography using chloroform-methanol to give the title compound (20mg, yield 43%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.69 (s, 3H), 4.03 (s, 3H), 4.03 (s, 3H),4.63 (s, 2H), 6.35 (d, J=5.4 Hz, 1H), 7.17-7.34 (m, 4H), 7.43 (d, J=8.3Hz, 1H), 7.50 (s, 1H), 7.71-7.80 (m, 1H), 7.86 (s, 1H), 8.22 (d, J=5.2Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 403 (M+1)⁺

Compound 2321-{3-[3-(6,7-Dimethoxy-quinolin-4-yloxy)-6-methyl-pyridin-2-yl]-phenyl}-ethanone

N,N-dimethylformamide (1 ml) and a 2 M aqueous potassium carbonatesolution (1 ml) were added to4-(2-iodo-6-methyl-pyridin-3-yloxy)-6,7-dimethoxy-quinoline (compound116) (50 mg), tetrakistriphenylphosphine palladium (14 mg), and3-acetylphenylboronic acid (67 mg) under an argon atmosphere, and themixture was stirred at 70° C. overnight. The reaction solution wascooled to room temperature, water was then added to the reactionsolution, and the mixture was extracted with ethyl acetate. The ethylacetate layer was then washed with water and was dried over anhydroussodium sulfate. The solvent was removed by distillation under thereduced pressure, and the residue was purified by thin layerchromatography using chloroform-methanol to give the title compound (49mg, yield 99%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.44 (s, 3H), 2.71 (s, 3H), 4.04 (s, 3H),4.08 (s, 3H), 6.33 (d, J=5.4 Hz, 1H), 7.28 (d, J=7.8 Hz, 1H), 7.37-7.58(m, 4H), 7.85 (d, J=7.8 Hz, 1H), 8.05 (d, J=7.8 Hz, 1H), 8.40 (d, J=5.4Hz, 1H), 8.51 (s, 1H)

Mass spectrometric value (ESI−MS, m/z): 415 (M+1)⁺

Compound 2333-[3-(6,7-Dimethoxy-quinolin-4-yloxy)-6-methyl-pyridin-2-yl]-benzamide

N,N-Dimethylformamide (1 ml) and a 2 M aqueous potassium carbonatesolution (1 ml) were added to4-(2-iodo-6-methyl-pyridin-3-yloxy)-6,7-dimethoxy-quinoline (compound116) (50 mg), tetrakistriphenylphosphine palladium (14 mg), and(3-aminocarbonyl)phenylboronic acid (58 mg) under an argon atmosphere,and the mixture was stirred at 70° C. for 5 hr. The reaction solutionwas cooled to room temperature, water was then added thereto, and themixture was extracted with ethyl acetate. The ethyl acetate layer wasthen washed with water and was dried over anhydrous sodium sulfate. Thesolvent was removed by distillation under the reduced pressure, and theresidue was purified by thin layer chromatography usingchloroform-methanol to give the title compound (49 mg, yield 100%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.70 (s, 3H), 4.03 (s, 3H), 4.07 (s, 3H),6.34 (d, J=5.1 Hz, 1H), 7.29 (s, 1H), 7.37 (dd, J=7.8, 7.8 Hz, 1H), 7.42(s, 1H), 7.50 (d, J=8.0 Hz, 1H), 7.53 (s, 1H), 7.70 (dd, J=1.4, 8.0 Hz,1H), 8.01 (d, J=8.0 Hz, 1H), 8.38-8.44 (m, 2H)

Mass spectrometric value (ESI−MS, m/z): 414 (M−1)⁻

Compound 2343-[3-(6,7-Dimethoxy-quinolin-4-yloxy)-6-methyl-pyridin-2-yl]-benzonitrile

N,N-Dimethylformamide (1 ml) and a 2 M aqueous potassium carbonatesolution (1 ml) were added to4-(2-iodo-6-methyl-pyridin-3-yloxy)-6,7-dimethoxy-quinoline (compound116) (50 mg), tetrakistriphenylphosphine palladium (14 mg) and3-cyanophenylboronic acid (52 mg) under an argon atmosphere, and themixture was stirred at 70° C. for 5 hr. The reaction solution was cooledto room temperature, water was then added thereto, and the mixture wasextracted with ethyl acetate. The ethyl acetate layer was then washedwith water and was dried over anhydrous sodium sulfate. The solvent wasremoved by distillation under the reduced pressure, and the residue waspurified by thin layer chromatography using chloroform-methanol to givethe title compound (43 mg, yield 92%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.70 (s, 3H), 4.04 (s, 3H), 4.07 (s, 3H),6.35 (d, J=5.4 Hz, 1H), 7.30 (d, J=8.3 Hz, 1H), 7.34-7.52 (m, 4H), 7.56(d, J=7.6 Hz, 1H), 8.10 (d, J=8.1 Hz, 1H), 8.30 (s, 1H), 8.43 (d, J=5.4Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 398 (M+1)⁺

Compound 2353-[3-(6,7-Dimethoxy-quinolin-4-yloxy)-6-methyl-pyridin-2-yl]-phenylamine

Toluene (1 ml), N,N-dimethylformamide (0.5 ml), and a saturated aqueoussodium hydrogencarbonate solution (0.5 ml) were added to4-(2-iodo-6-methyl-pyridin-3-yloxy)-6,7-dimethoxy-quinoline (compound116) (50 mg), tetrakistriphenylphosphine palladium (28 mg), and3-aminophenylboronic acid (162 mg) under an argon atmosphere, and themixture was stirred at 80° C. overnight. The reaction solution wascooled to room temperature, water was then added to the reactionsolution, and the mixture was extracted with chloroform. The ethylacetate layer was then washed with water and was dried over anhydrousmagnesium sulfate. The solvent was removed by distillation under thereduced pressure, and the residue was purified by thin layerchromatography using chloroform-methanol to give the title compound (39mg, yield 85%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.69 (s, 3H), 4.04 (s, 3H), 4.05 (s, 3H),6.39 (d, J=5.4 Hz, 1H), 6.59 (dd, J=2.2, 7.8 Hz, 1H), 7.02 (dd, J=7.8,7.8 Hz, 1H), 7.14-7.25 (m, 3H), 7.44 (d, J=8.3 Hz, 1H), 7.48-7.57 (m,2H), 8.42 (d, J=5.4 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 388 (M+1)⁺

Compound 236N-{3-[3-(6,7-Dimethoxy-quinolin-4-yloxy)-6-methyl-pyridin-2-yl]-phenyl}-acetamide

Toluene (1 ml) and a saturated aqueous sodium hydrogencarbonate solution(0.5 ml) were added to4-(2-iodo-6-methyl-pyridin-3-yloxy)-6,7-dimethoxy-quinoline (compound116) (50 mg), tetrakistriphenylphosphine palladium (14 mg), and(3-acetylamino)-phenylboronic acid (97 mg) under an argon atmosphere,and the mixture was stirred at 80° C. overnight. The reaction solutionwas cooled to room temperature, a 1 N aqueous sodium hydroxide solutionwas then added thereto, and the mixture was extracted with chloroform.The chloroform layer was then washed with water and was dried overanhydrous sodium sulfate. The solvent was removed by distillation underthe reduced pressure, and the residue was purified by thin layerchromatography using chloroform-methanol to give the title compound (3.6mg, yield 7%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.09 (s, 3H), 2.69 (s, 3H), 4.04 (s, 3H),4.08 (s, 3H), 6.35 (d, J=5.4 Hz, 1H), 7.12-7.29 (m, 3H), 7.33 (d, J=7.6Hz, 1H), 7.46 (d, J=8.3 Hz, 1H), 7.49 (s, 1H), 7.54 (d, J=7.6 Hz, 1H),7.58 (s, 1H), 8.17 (s, 1H), 8.40 (d, J=5.6 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 430 (M+1)⁺

Compound 2373-[3-(6,7-Dimethoxy-quinolin-4-yloxy)-6-methyl-pyridin-2-yl]-phenol

Toluene (1 ml) and a saturated aqueous sodium hydrogencarbonate solution(0.5 ml) were added to4-(2-iodo-6-methyl-pyridin-3-yloxy)-6,7-dimethoxy-quinoline (compound116) (50 mg), tetrakistriphenylphosphine palladium (14 mg), and3-hydroxyphenylboronic acid (81 mg) under an argon atmosphere, and themixture was stirred at 80° C. overnight. The reaction solution wascooled to room temperature, water was then added thereto, and themixture was extracted with chloroform. The chloroform layer was thenwashed with water and was dried over anhydrous sodium sulfate. Thesolvent was removed by distillation under the reduced pressure, and theresidue was purified by thin layer chromatography usingchloroform-methanol to give the title compound (6.8 mg, yield 15%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.67 (s, 3H), 3.82 (s, 3H), 3.98 (s, 3H),6.36 (d, J=5.4 Hz, 1H), 6.92 (dd, J=1.7, 7.8 Hz, 1H), 6.97 (s, 1H), 7.17(d, J=8.3 Hz, 1H), 7.23-7.32 (m, 2H), 7.34 (d, J=7.8 Hz, 1H), 7.37 (s,1H), 7.44 (s, 1H), 7.48 (d, J=7.8 Hz, 1H), 7.94 (d, J=5.6 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 389 (M+1)⁺

Compound 2386,7-Dimethoxy-4-[2-(3-methoxy-phenyl)-6-methyl-pyridin-3-yloxy]-quinoline

4-[(2-Iodo-6-methyl-3-pyridyl)oxy]-6,7-dimethoxy-quinoline (compound116) (84 mg), 3-methoxyphenylboronic acid (152 mg), andtetrakistriphenylphosphine palladium (12 mg) were dissolved in toluene(1 ml) to prepare a solution. A saturated aqueous sodiumhydrogencarbonate solution (1 ml) was added to the solution, and themixture was stirred at 80° C. for 3 hr. The reaction solution wasfiltered, the solvent was then removed by distillation under the reducedpressure, and the residue was purified by column chromatography usingmethanol-chloroform to give the title compound (79 mg, yield 99%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.65 (s, 3H), 3.62 (s, 3H), 3.99 (s, 3H),4.00 (s, 3H), 6.33 (d, J=5.4 Hz, 1H), 6.78 (m, 1H), 7.14-7.19 (m, 2H),7.36-7.45 (m, 4H), 7.48 (s, 1H), 8.39 (d, J=5.4 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 403 (M+1)⁺

Compound 2394-[2-(3-Ethoxy-phenyl)-6-methyl-pyridin-3-yloxy]-6,7-dimethoxy-quinoline

N,N-Dimethylformamide (1 ml) and a 2 M aqueous potassium carbonatesolution (1 ml) were added to4-(2-iodo-6-methyl-pyridin-3-yloxy)-6,7-dimethoxy-quinoline (compound116) (50 mg), tetrakistriphenylphosphine palladium (14 mg), and3-ethoxyphenylboronic acid (59 mg) under an argon atmosphere, and themixture was stirred at 70° C. for 5 hr. The reaction solution was cooledto room temperature, water was then added thereto, and the mixture wasextracted with ethyl acetate. The ethyl acetate layer was then washedwith water and was dried over anhydrous sodium sulfate, the solvent wasremoved by distillation under the reduced pressure, and the residue waspurified by thin layer chromatography using chloroform-methanol to givethe title compound (43 mg, yield 87%).

¹H-NMR (CDCl₃, 400 MHz): δ 1.28 (t, J=6.8 Hz, 3H), 2.69 (s, 3H), 3.87(q, J=6.8 Hz, 2H), 4.04 (s, 3H), 4.05 (s, 3H), 6.36 (d, J=5.4 Hz, 1H),6.79 (dd, J=1.7, 7.1 Hz, 1H), 7.17 (dd, J=8.3, 8.3 Hz, 1H), 7.16 (d,J=8.3 Hz, 1H), 7.36-7.51 (m, 4H), 7.53 (s, 1H), 8.42 (d, J=5.4 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 439 (M+Na)⁺

Compound 2404-[2-(3-Fluoro-phenyl)-6-methyl-pyridin-3-yloxy]-6,7-dimethoxy-quinoline

N,N-Dimethylformamide (1 ml) and a 2 M aqueous potassium carbonatesolution (1 ml) were added to4-(2-iodo-6-methyl-pyridin-3-yloxy)-6,7-dimethoxy-quinoline (compound116) (50 mg), tetrakistriphenylphosphine palladium (14 mg), and3-fluorophenylboronic acid (50 mg) under an argon atmosphere, and themixture was stirred at 70° C. for 5 hr. The reaction solution was cooledto room temperature, water was then added thereto, and the mixture wasextracted with ethyl acetate. The ethyl acetate layer was then washedwith water and was dried over anhydrous sodium sulfate. The solvent wasremoved by distillation under the reduced pressure, and the residue waspurified by thin layer chromatography using chloroform-methanol to givethe title compound (43 mg, yield 87%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.70 (s, 3H), 4.06 (s, 3H), 4.06 (s, 3H),6.39 (d, J=5.4 Hz, 1H), 6.94-7.00 (m, 1H), 7.20-7.32 (m, 2H), 7.44-7.72(m, 5H), 8.44 (d, J=5.6 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 413 (M+Na)⁺

Compound 2414-[2-(3-Chloro-phenyl)-6-methyl-pyridin-3-yloxy]-6,7-dimethoxy-quinoline

4-[(2-Iodo-6-methyl-3-pyridyl)oxy]-6,7-dimethoxy-quinoline (compound116) (84 mg), 3-chlorophenylboronic acid (156 mg),tetrakistriphenylphosphine palladium (12 mg) were dissolved in toluene(1 ml) to prepare a solution. A saturated aqueous sodiumhydrogencarbonate solution (1 ml) was added to the solution, and themixture was stirred at 80° C. for 3 hr. The reaction solution wasfiltered, and the solvent was then removed by distillation under thereduced pressure. The residue was purified by column chromatographyusing methanol-chloroform to give the title compound (59 mg, yield 73%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.65 (s, 3H), 4.01 (s, 3H), 4.02 (s, 3H),6.30 (d, J=5.4 Hz, 1H), 7.15-7.22 (m, 3H), 7.37 (s, 1H), 7.44 (d, J=8.3Hz, 1H), 7.48 (s, 1H), 7.70 (m, 1H), 7.92 (m, 1H), 8.39 (d, J=5.4 Hz,1H)

Mass spectrometric value (ESI−MS, m/z): 407 (M+1)⁺

Compound 2426,7-Dimethoxy-4-(6-methyl-2-p-tolyl-pyridin-3-yloxy)-quinoline

4-[(2-Iodo-6-methyl-3-pyridyl)oxy]-6,7-dimethoxy-quinoline (compound116) (84 mg), 4-methylphenylboronic acid (136 mg), andtetrakistriphenylphosphine palladium (12 mg) were dissolved in toluene(1 ml) to prepare a solution. A saturated aqueous sodiumhydrogencarbonate solution (1 ml) was added to the solution, and themixture was stirred at 80° C. for 3 hr. The reaction solution wasfiltered, then the solvent was removed by distillation under the reducedpressure, and the residue was purified by column chromatography usingmethanol-chloroform to give the title compound (77 mg, yield 100%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.24 (s, 3H), 2.64 (s, 3H), 4.00 (s, 3H),4.01 (s, 3H), 6.33 (d, J=5.1 Hz, 1H), 7.06 (d, J=8.0 Hz, 2H), 7.15 (d,J=8.3 Hz, 1H), 7.37 (s, 1H), 7.38 (d, J=8.1 Hz, 1H), 7.49 (s, 1H), 7.74(d, J=8.3 Hz, 2H), 8.39 (d, J=5.4 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 387 (M+1)⁺

Compound 2434-[2-(4-Isopropyl-phenyl)-6-methyl-pyridin-3-yloxy]-6,7-dimethoxy-quinoline

4-[(2-Iodo-6-methyl-3-pyridyl)oxy]-6,7-dimethoxy-quinoline (compound116) (84 mg), 4-isopropylphenylboronic acid (164 mg), andtetrakistriphenylphosphine palladium (12 mg) were dissolved in toluene(1 ml) to prepare a solution. A saturated aqueous sodiumhydrogencarbonate solution (1 ml) was added to the solution, and themixture was stirred at 80° C. for 3 hr. The reaction solution wasfiltered, the solvent was then removed by distillation under the reducedpressure, and the residue was purified by column chromatography usingmethanol-chloroform to give the title compound (59 mg, yield 72%).

¹H-NMR (CDCl₃, 400 MHz): δ 1.10 (d, J=6.8 Hz, 6H), 2.60 (s, 3H), 2.76(m, 1H), 3.95 (s, 3H), 3.96 (s, 3H), 6.32 (d, J=5.4 Hz, 1H), 7.07-7.11(m, 3H), 7.33 (d, J=8.3 Hz, 1H), 7.34 (s, 1H), 7.44 (s, 1H), 7.72 (d,J=8.3 Hz, 2H), 8.36 (d, 3=5.1 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 415 (M+1)⁺

Compound 2444-[2-(4-Butyl-phenyl)-6-methyl-pyridin-3-yloxy]-6,7-dimethoxy-quinoline

4-[(2-Iodo-6-methyl-3-pyridyl)oxy]-6,7-dimethoxy-quinoline (compound116) (84 mg), 4-n-butylphenylboronic acid (178 mg), andtetrakistriphenylphosphine palladium (12 mg) were dissolved in toluene(1 ml) to prepare a solution. A saturated aqueous sodiumhydrogencarbonate solution (1 ml) was added to the solution, and themixture was stirred at 80° C. for 3 hr. The reaction solution wasfiltered, the solvent was then removed by distillation under the reducedpressure, and the residue was purified by column chromatography usingmethanol-chloroform to give the title compound (55 mg, yield 64%).

¹H-NMR (CDCl₃, 400 MHz): δ 0.79 (t, J=7.3 Hz, 3H), 1.18 (m, 2H), 1.44(m, 2H), 2.46 (t, J=7.6 Hz, 2H), 2.60 (s, 3H), 3.95 (s, 3H), 3.96 (s,3H), 6.30 (d, J=5.4 Hz, 1H), 7.02 (d, J=8.1 Hz, 2H), 7.11 (d, J=8.3 Hz,1H), 7.34-7.35 (m, 2H), 7.44 (s, 1H), 7.70 (d, J=8.3 Hz, 2H), 8.35 (d,J=5.4 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 429 (M+1)⁺

Compound 245{4-[3-(6,7-Dimethoxy-quinolin-4-yloxy)-6-methyl-pyridin-2-yl]-phenyl}-methanol

Toluene (1 ml) and a saturated aqueous sodium hydrogencarbonate solution(0.5 ml) were added to4-(2-iodo-6-methyl-pyridin-3-yloxy)-6,7-dimethoxy-quinoline (compound116) (50 mg), tetrakistriphenylphosphine palladium (14 mg), and(4-hydroxymethyl)phenylboronic acid (90 mg) under an argon atmosphere,and the mixture was stirred at 80° C. for 5 hr. The reaction solutionwas cooled to room temperature, an aqueous sodium hydroxide solution wasthen added thereto, and the mixture was extracted with ethyl acetate.The ethyl acetate layer was then washed with water and was dried overanhydrous sodium sulfate. The solvent was removed by distillation underthe reduced pressure, and the residue was purified by thin layerchromatography using chloroform-methanol to give the title compound (11mg, yield 24%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.69 (s, 3H), 4.03 (s, 3H), 4.03 (s, 3H),4.63 (s, 2H), 6.35 (d, J=5.4 Hz, 1H), 7.22 (d, J=8.3 Hz, 1H), 7.28 (d,J=8.6 Hz, 1H), 7.40-7.48 (m, 2H), 7.51 (s, 1H), 7.58 (d, J=8.3 Hz, 1H),7.85 (d, J=8.6 Hz, 2H), 8.41 (d, J=5.4 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 403 (M+1)⁺

Compound 2461-{4-[3-(6,7-Dimethoxy-quinolin-4-yloxy)-6-methyl-pyridin-2-yl]-phenyl}-ethanone

N,N-Dimethylformamide (1 ml) and a 2 M aqueous potassium carbonatesolution (0.5 ml) were added to4-(2-iodo-6-methyl-pyridin-3-yloxy)-6,7-dimethoxy-quinoline (compound116) (50 mg), tetrakistriphenylphosphine palladium (14 mg), and4-acetylphenylboronic acid (97 mg) under an argon atmosphere, and themixture was stirred at 70° C. overnight. The reaction solution wascooled to room temperature, water was then added thereto, and themixture was extracted with ethyl acetate. The ethyl acetate layer wasthen washed with water and was dried over anhydrous sodium sulfate. Thesolvent was removed by distillation under the reduced pressure, and theresidue was purified by thin layer chromatography usingchloroform-methanol to give the title compound (26 mg, yield 52%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.55 (s, 3H), 2.71 (s, 3H), 4.05 (s, 3H),4.06 (s, 3H), 6.38 (d, J=5.4 Hz, 1H), 7.29 (d, J=8.5 Hz, 1H), 7.34-7.60(m, 3H), 7.88 (d, J=8.3 Hz, 2H), 7.97 (d, J=8.3 Hz, 2H), 8.42 (d, J=5.6Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 437 (M+Na)⁺

Compound 247{4-[3-(6,7-Dimethoxy-quinolin-4-yloxy)-6-methyl-pyridin-2-yl]-phenyl}-dimethyl-amine

Toluene (1 ml), N,N-dimethylformamide (0.5 ml) and a saturated aqueoussodium hydrogencarbonate solution (0.5 ml) were added to4-(2-iodo-6-methyl-pyridin-3-yloxy)-6,7-dimethoxy-quinoline (compound116) (50 mg), tetrakistriphenylphosphine palladium (28 mg), and4-dimethylaminophenylboronic acid (196 mg) under an argon atmosphere,and the mixture was stirred at 80° C. overnight. The reaction solutionwas cooled to room temperature, water was then added thereto, and themixture was extracted with chloroform. The chloroform layer was thenwashed with water and was dried over anhydrous magnesium sulfate. Thesolvent was removed by distillation under the reduced pressure, and theresidue was purified by column chromatography using chloroform-methanolto give the title compound (39 mg, yield 80%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.66 (s, 3H), 2.91 (s, 6H), 4.05 (s, 6H),6.37 (d, J=5.4 Hz, 1H), 6.59 (d, J=9.0 Hz, 2H), 7.09 (d, J=8.3 Hz, 1H),7.38 (d, J=8.3 Hz, 1H), 7.48 (s, 1H), 7.59 (s, 1H), 7.84 (d, J=9.0 Hz,2H), 8.41 (d, J=5.4 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 438 (M+Na)⁺

Compound 248{4-[3-(6,7-Dimethoxy-quinolin-4-yloxy)-6-methyl-pyridin-2-yl]-phenol

N,N-Dimethylformamide (1 ml) and a 2 M aqueous potassium carbonatesolution (0.5 ml) were added to4-(2-iodo-6-methyl-pyridin-3-yloxy)-6,7-dimethoxy-quinoline (compound116) (50 mg), tetrakistriphenylphosphine palladium (14 mg), and4-hydroxyphenylboronic acid (81 mg) under an argon atmosphere, and themixture was stirred at 70° C. overnight. The reaction solution wascooled to room temperature, water was then added thereto, and themixture was extracted with ethyl acetate. The ethyl acetate layer wasthen washed with water and was dried over anhydrous sodium sulfate. Thesolvent was removed by distillation under the reduced pressure, and theresidue was purified by thin layer chromatography usingchloroform-methanol to give the title compound (34 mg, yield 75%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.66 (s, 3H), 3.99 (s, 3H), 4.03 (s, 3H),6.34 (d, J=5.6 Hz, 1H), 6.69 (d, J=8.8 Hz, 2H), 7.17 (d, J=8.3 Hz, 1H),7.40-7.46 (m, 2H), 7.52 (s, 1H), 7.68 (d, J=8.8 Hz, 2H), 8.38 (d, J=5.4Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 389 (M+1)⁺

Compound 2496,7-Dimethoxy-4-[2-(4-methoxy-phenyl)-6-methyl-pyridin-3-yloxy]-quinoline

4-[(2-Iodo-6-methyl-3-pyridyl)oxy]-6,7-dimethoxy-quinoline (compound116) (84 mg), 4-methoxyphenylboronic acid (152 mg), andtetrakistriphenylphosphine palladium (12 mg) were dissolved in toluene(1 ml) to prepare a solution. A saturated aqueous sodiumhydrogencarbonate solution (1 ml) was added to the solution, and themixture was stirred at 80° C. for 3 hr. The reaction solution wasfiltered, and the solvent was then removed by distillation under thereduced pressure. The residue was purified by column chromatographyusing methanol-chloroform to give the title compound (64 mg, yield 80%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.59 (s, 3H), 3.66 (s, 3H), 3.96 (s, 3H),3.96 (s, 3H), 6.28 (d, J=5.1 Hz, 1H), 6.73 (d, J=8.8 Hz, 2H), 7.08 (d,J=8.1 Hz, 1H), 7.31-7.34 (m, 2H), 7.46 (s, 1H), 7.77 (d, J=8.8 Hz, 2H),8.34 (d, J=5.4 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 403 (M+1)⁺

Compound 2506,7-Dimethoxy-4-[6-methyl-2-(4-phenoxy-phenyl)-pyridin-3-yloxy]-quinoline

Toluene (1 ml) and a saturated aqueous sodium hydrogencarbonate solution(0.5 ml) were added to4-(2-iodo-6-methyl-pyridin-3-yloxy)-6,7-dimethoxy-quinoline (compound116) (50 mg), tetrakistriphenylphosphine palladium (14 mg), and4-phenoxyphenylboronic acid (81 mg) under an argon atmosphere, and themixture was stirred at 70° C. overnight. The reaction solution wascooled to room temperature, water was then added thereto, and themixture was extracted with ethyl acetate. The ethyl acetate layer wasthen washed with water and was dried over anhydrous sodium sulfate. Thesolvent was removed by distillation under the reduced pressure, and theresidue was purified by thin layer chromatography usingchloroform-methanol to give the title compound (53 mg, yield 96%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.68 (s, 3H), 4.02 (s, 3H), 4.05 (s, 3H),6.37 (d, J=5.1 Hz, 1H), 6.85-6.91 (m, 4H), 7.08 (t, J=7.6 Hz, 1H), 7.20(d, J=8.0 Hz, 1H), 7.25-7.33 (m, 2H), 7.38-7.52 (m, 3H), 7.84 (d, J=8.8Hz, 2H), 8.43 (d, J=5.4 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 465 (M+1)⁺

Compound 2514-[2-(4-Fluoro-phenyl)-6-methyl-pyridin-3-yloxy]-6,7-dimethoxy-quinoline

4-[(2-Iodo-6-methyl-3-pyridyl)oxy]-6,7-dimethoxy-quinoline (compound116) (84 mg), 4-fluorophenylboronic acid (140 mg), andtetrakistriphenylphosphine palladium (12 mg) were dissolved in toluene(1 ml) to prepare a solution. A saturated aqueous sodiumhydrogencarbonate solution (1 ml) was added to the solution, and themixture was stirred at 80° C. for 3 hr. The reaction solution wasfiltered, the solvent was then removed by distillation under the reducedpressure, and the residue was purified by column chromatography usingmethanol-chloroform to give the title compound (64 mg, yield 82%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.60 (s, 3H), 3.95 (s, 3H), 3.96 (s, 3H),6.28 (d, J=5.4 Hz, 1H), 6.90 (m, 2H), 7.14 (d, J=8.3 Hz, 1H), 7.34 (s,1H), 7.36 (d, J=8.0 Hz, 1H), 7.41 (s, 1H), 7.79 (m, 2H), 8.36 (d, J=5.1Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 391 (M+1)⁺

Compound 2524-[2-(4-Chlorophenyl)-6-methyl-pyridin-3-yloxy]-6,7-dimethoxy-quinoline

4-[(2-Iodo-6-methyl-3-pyridyl)oxy]-6,7-dimethoxy-quinoline (compound116) (84 mg), 4-chlorophenylboronic acid (156 mg), andtetrakistriphenylphosphine palladium (12 mg) were dissolved in toluene(1 ml) to prepare a solution. A saturated aqueous sodiumhydrogencarbonate solution (1 ml) was added to the solution, and themixture was stirred at 80° C. for 3 hr. The reaction solution wasfiltered, the solvent was then removed by distillation under the reducedpressure, and the residue was purified by column chromatography usingmethanol-chloroform to give the title compound (74 mg, yield 91%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.60 (s, 3H), 3.95 (s, 3H), 3.96 (s, 3H),6.27 (d, J=5.4 Hz, 1H), 7.14 (d, J=8.3 Hz, 1H), 7.19 (m, 2H), 7.34-7.40(m, 3H), 7.75 (m, 2H), 8.36 (d, J=5.4 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 407 (M+1)⁺

Compound 2534-[2-(2,6-Dichloro-phenyl)-6-methyl-pyridin-3-yloxy]-6,7-dimethoxy-quinoline

4-[(2-Iodo-6-methyl-3-pyridyl)oxy]-6,7-dimethoxy-quinoline (compound116) (84 mg), 2,6-dichlorophenylboronic acid (191 mg), andtetrakistriphenylphosphine palladium (12 mg) were dissolved in toluene(1 ml) to prepare a solution. A saturated aqueous sodiumhydrogencarbonate solution (1 ml) was added to the solution, and themixture was stirred at 80° C. for 3 hr. The reaction solution wasfiltered, the solvent was then removed by distillation under the reducedpressure, and the residue was purified by column chromatography usingmethanol-chloroform to give the title compound (79 mg, yield 90%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.64 (s, 3H), 3.97 (s, 3H), 3.97 (s, 3H),6.38 (d, J=5.4 Hz, 1H), 7.09 (dd, J=2.7, 8.6 Hz, 1H), 7.19 (d, J=8.6 Hz,1H), 7.28 (d, J=8.8 Hz, 1H), 7.31 (s, 1H), 7.35 (d, J=2.7 Hz, 1H), 7.39(s, 1H), 7.49 (d, J=8.3 Hz, 1H), 8.41 (d, J=5.1 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 441 (M+1)⁺

Compound 2544-[2-(3,5-Difluoro-phenyl)-6-methyl-pyridin-3-yloxy]-6,7-dimethoxy-quinoline

N,N-Dimethylformamide (1 ml) and a 2 M aqueous potassium carbonatesolution (1 ml) were added to4-(2-iodo-6-methyl-pyridin-3-yloxy)-6,7-dimethoxy-quinoline (compound116) (50 mg), tetrakistriphenylphosphine palladium (14 mg), and3,5-difluorophenylboronic acid (56 mg) under an argon atmosphere, andthe mixture was stirred at 70° C. for 5 hr. The reaction solution wascooled to room temperature, water was then added thereto, and themixture was extracted with ethyl acetate. The ethyl acetate layer wasthen washed with water and was dried over anhydrous sodium sulfate. Thesolvent was removed by distillation under the reduced pressure, and theresidue was purified by thin layer chromatography usingchloroform-methanol to give the title compound (23 mg, yield 47%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.70 (s, 3H), 4.07 (s, 6H), 6.36 (d, J=5.6Hz, 1H), 6.68-6.79 (m, 1H), 7.29 (d, J=8.3 Hz, 1H), 7.41-7.63 (m, 5H),8.43 (d, J=5.4 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 409 (M+1)⁺

Compound 2556,7-Dimethoxy-4-(6-methyl-2-thiophen-3-yl-pyridin-3-yloxy)-quinoline

4-[(2-Iodo-6-methyl-3-pyridyl)oxy]-6,7-dimethoxy-quinoline (compound116) (84 mg), 3-thiopheneboronic acid (128 mg), andtetrakistriphenylphosphine palladium (12 mg) were dissolved in toluene(1 ml) to prepare a solution. A saturated aqueous sodiumhydrogencarbonate solution (1 ml) was added to the solution, and themixture was stirred at 80° C. for 3 hr. The reaction solution wasfiltered, the solvent was then removed by distillation under the reducedpressure, and the residue was purified by column chromatography usingmethanol-chloroform to give the title compound (58 mg, yield 77%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.65 (s, 3H), 4.06 (s, 3H), 4.08 (s, 3H),6.42 (d, J=5.6 Hz, 1H), 7.16 (d, J=8.3 Hz, 1H), 7.23 (m, 1H), 7.24 (s,1H), 7.39 (d, J=8.3 Hz, 1H), 7.61 (s, 1H), 7.69 (d, J=5.1 Hz, 1H), 7.88(d, J=2.7 Hz, 1H), 8.41 (d, J=5.6 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 379 (M+1)⁺

Compound 2564-[2-(1,5-Dimethyl-1H-pyrazol-3-yl)-6-methyl-pyridin-3-yloxy]-6,7-dimethoxy-quinoline

3-Benzyloxy-6-methyl-pyridine-2-carbaldehyde (452 mg) was dissolved intetrahydrofuran (15 ml) to prepare a solution. A 1-propynylmagnesiumbromide/0.5 M tetrahydrofuran solution (6 ml) was added to the solutionat −78° C., and the mixture was stirred at room temperature for 2 hr.Water was added to the reaction solution, and the mixture was extractedwith ethyl acetate. The ethyl acetate layer was then washed with waterand was dried over anhydrous sodium sulfate, and the solvent was removedby distillation under the reduced pressure. The residue was used in thenext reaction without purification.

The residue was dissolved in chloroform (15 ml) to prepare a solution.Manganese dioxide (1.36 g) was added to the solution, and the mixturewas stirred at room temperature overnight. The reaction solution wasfiltered, and the solvent was removed by distillation under the reducedpressure. The residue (563 mg) was used in the next reaction withoutpurification.

A part (240 mg) of the residue was dissolved in N,N-dimethylformamide (7ml) to prepare a solution. Hydrazine monohydrate (0.15 ml) was added tothe solution, and the mixture was stirred at room temperature overnight.Water was added to the reaction solution, and the mixture was extractedwith ethyl acetate. The ethyl acetate layer was then washed with waterand was dried over anhydrous sodium sulfate. The solvent was removed bydistillation under the reduced pressure, and the residue was used in thenext reaction without purification.

The residue was dissolved in N,N-dimethylformamide (5 ml) to prepare asolution. Potassium carbonate (339 mg) and methyl iodide (0.15 ml) wereadded to the solution under ice cooling, and the mixture was stirred atroom temperature overnight. Water was added to the reaction solution,and the mixture was extracted with ethyl acetate. The ethyl acetatelayer was then washed with water and was dried over anhydrous sodiumsulfate. The solvent was removed by distillation under the reducedpressure, and the residue was used in the next reaction withoutpurification.

Trifluoroacetic acid (3 ml) and methanesulfonic acid (0.3 ml) were addedto the residue, and the mixture was stirred at room temperatureovernight. The solvent was removed by distillation under the reducedpressure. Water was then added to the reaction solution, and the mixturewas extracted with ethyl acetate. The organic layer was washed with anaqueous sodium hydrogencarbonate solution and water and was dried overanhydrous sodium sulfate. The solvent was removed by distillation underthe reduced pressure, and the residue was purified by columnchromatography using acetone-chloroform to give2-(1,5-dimethyl-1H-pyrazol-3-yl)-6-methyl-pyridin-3-ol (60 mg, yield32%) (5 steps).

2-(1,5-Dimethyl-1H-pyrazol-3-yl)-6-methyl-pyridin-3-ol (111 mg),4-chloro-6,7-dimethoxyquinoline (218 mg), and 4-dimethylaminopyridine(130 mg) were suspended in o-dichlorobenzene (5 ml), and the suspensionwas stirred at 160° C. for 2 days. The reaction solution was cooled toroom temperature, and the solvent was then removed by distillation underthe reduced pressure. The residue was purified by thin layerchromatography using methanol-chloroform to give the title compound (9mg, yield 40%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.13 (s, 3H), 2.71 (s, 3H), 3.75 (s, 3H),4.06 (s, 3H), 4.07 (s, 3H), 6.33 (d, J=5.4 Hz, 1H), 6.41 (s, 1H), 7.17(d, J=8.3 Hz, 1H), 7.39 (d, J=8.0 Hz, 1H), 7.44 (s, 1H), 7.65 (s, 1H),8.42 (d, J=5.1 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 413 (M+Na)⁺

Compound 2574-[2-(2,5-Dimethyl-2H-pyrazol-3-yl)-6-methyl-pyridin-3-yloxy]-6,7-dimethoxy-quinoline

3-Benzyloxy-6-methyl-pyridine-2-carbaldehyde (452 mg) was dissolved intetrahydrofuran (15 ml) to prepare a solution. A 1-propynylmagnesiumbromide/0.5 M tetrahydrofuran solution (6 ml) was added to the solutionat −78° C., and the mixture was stirred at room temperature for 2 hr.Water was added to the reaction solution, and the mixture was extractedwith ethyl acetate, and the ethyl acetate layer was then washed withwater and was dried over anhydrous sodium sulfate. The solvent wasremoved by distillation under the reduced pressure, and the residue wasused in the next reaction without purification.

The residue was dissolved in chloroform (15 ml) to prepare a solution.Manganese dioxide (1.36 g) was added to the solution, and the mixturewas stirred at room temperature overnight. The reaction solution wasfiltered, and the solvent was removed by distillation under the reducedpressure. The residue (563 mg) was used in the next reaction withoutpurification.

A part (240 mg) of the residue was dissolved in N,N-dimethylformamide (7ml) to prepare a solution. Hydrazine monohydrate (0.15 ml) was added tothe solution, and the mixture was stirred at room temperature overnight.Water was added to the reaction solution, and the mixture was extractedwith ethyl acetate. The ethyl acetate layer was then washed with waterand was dried over anhydrous sodium sulfate. The solvent was removed bydistillation under the reduced pressure, and the residue was used in thenext reaction without purification.

The residue was dissolved in N,N-dimethylformamide (5 ml) to prepare asolution. Potassium carbonate (339 mg) and methyl iodide (0.15 ml) wereadded to the solution under ice cooling, and the mixture was stirred atroom temperature overnight. Water was added to the reaction solution,and the mixture was extracted with ethyl acetate. The ethyl acetatelayer was then washed with water and was dried over anhydrous sodiumsulfate. The solvent was removed by distillation under the reducedpressure, and the residue was used in the next reaction withoutpurification.

Trifluoroacetic acid (3 ml) and methanesulfonic acid (0.3 ml) were addedto the residue, and the mixture was stirred at room temperatureovernight. The solvent was removed by distillation under the reducedpressure. Water was then added to the reaction solution, and the mixturewas extracted with ethyl acetate. The organic layer was washed with anaqueous sodium hydrogencarbonate solution and was washed with water andwas dried over anhydrous sodium sulfate. The solvent was removed bydistillation under the reduced pressure, and the residue was purified bycolumn chromatography using acetone-chloroform to give2-(2,5-dimethyl-2H-pyrazol-3-yl)-6-methyl-pyridin-3-ol (38 mg, yield21%) (5 steps).

2-(2,5-Dimethyl-2H-pyrazol-3-yl)-6-methyl-pyridin-3-ol (33 mg),4-chloro-6,7-dimethoxyquinoline (109 mg), and 4-dimethylaminopyridine(66 mg) were dissolved in dimethyl sulfoxide (5 ml) to prepare asolution. Cesium carbonate (165 mg) was added to the solution, and themixture was stirred at 140° C. for 4 hr. The reaction solution wascooled to room temperature, water was then added to the reactionsolution, and the mixture was extracted with ethyl acetate. The ethylacetate layer was then washed with water and was dried over anhydroussodium sulfate. The solvent was removed by distillation under thereduced pressure, and the residue was purified by thin layerchromatography using methanol-chloroform to give the title compound (15mg, yield 23%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.12 (s, 3H), 2.66 (s, 3H), 4.03 (s, 3H),4.06 (s, 3H), 4.08 (s, 3H), 6.27 (s, 1H), 6.37 (d, J=5.4 Hz, 1H), 7.22(d, J=8.3 Hz, 1H), 7.43 (d, J=8.3 Hz, 1H), 7.45 (s, 1H), 7.48 (s, 1H),8.48 (d, J=5.1 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 413 (M+Na)⁺

Compound 2586,7-Dimethoxy-4-[6-methyl-2-(3-methyl-isoxazol-5-yl)-pyridin-3-yloxy]-quinoline

3-Benzyloxy-6-methyl-pyridine-2-carbaldehyde (452 mg) was dissolved intetrahydrofuran (15 ml) to prepare a solution. A 1-propynylmagnesiumbromide/0.5 M tetrahydrofuran solution (6 ml) was added to the solutionat −78° C., and the mixture was stirred at room temperature for 2 hr.Water was added to the reaction solution, and the mixture was extractedwith ethyl acetate. The ethyl acetate layer was then washed with waterand was dried over anhydrous sodium sulfate. The solvent was removed bydistillation under the reduced pressure, and the residue was used in thenext reaction without purification.

The residue was dissolved in chloroform (15 ml) to prepare a solution.Manganese dioxide (1.36 g) was added to the solution, and the mixturewas stirred at room temperature overnight. The reaction solution wasfiltered, the solvent was removed by distillation under the reducedpressure, and the residue (563 mg) was used in the next reaction withoutpurification.

A part (117 mg) of the residue was dissolved in N,N-dimethylformamide (4ml) to prepare a solution. Hydroxyamine hydrochloride (298 mg) andtriethylamine (0.6 ml) were added to the solution, and the mixture wasstirred at room temperature for 4 hr. Water was added to the reactionsolution, and the mixture was extracted with ethyl acetate. The ethylacetate layer was then washed with water and was dried over anhydroussodium sulfate. The solvent was removed by distillation under thereduced pressure, and the residue was used in the next reaction withoutpurification.

Trifluoroacetic acid (2 ml) and methanesulfonic acid (0.2 ml) were addedto the residue, and the mixture was stirred at room temperatureovernight. The solvent was removed by distillation under the reducedpressure, water was then added to the reaction solution, and the mixturewas extracted with ethyl acetate. The organic layer was washed with anaqueous sodium hydrogencarbonate solution and water and was dried overanhydrous sodium sulfate. The solvent was removed by distillation underthe reduced pressure, and the residue (84 mg) was used in the nextreaction without purification.

A part (56 mg) of the residue, 4-chloro-6,7-dimethoxyquinoline (200 mg),and 4-dimethylaminopyridine (158 mg) were dissolved in o-dichlorobenzene(4 ml) to prepare a solution which was then stirred at 140° C. for 5 hr.The reaction solution was cooled to room temperature, the solvent wasthen removed by distillation under the reduced pressure, and the residuewas purified by thin layer chromatography using methanol-chloroform togive the title compound (16 mg, yield 10%) (5 steps).

¹H-NMR (CDCl₃, 400 MHz): δ 2.26 (s, 3H), 2.71 (s, 3H), 4.05 (s, 3H),4.07 (s, 3H), 6.41 (d, J=5.4 Hz, 1H), 6.62 (s, 1H), 7.30 (d, J=8.5 Hz,1H), 7.45 (d, J=8.3 Hz, 1H), 7.47 (s, 1H), 7.57 (s, 1H), 8.49 (d, J=5.4Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 400 (M+Na)⁺

Compound 2596,7-Dimethoxy-4-(6-methyl-2-thiazol-2-yl-pyridin-3-yloxy)-quinoline

N,N-Dimethylformamide (1 ml) was added to4-(2-iodo-6-methyl-pyridin-3-yloxy)-6,7-dimethoxy-quinoline (compound116) (50 mg), tetrakistriphenylphosphine palladium (14 mg),tri-n-butyl-(thiazol-2-yl)-tin (132 mg), and copper(II) oxide (1.9 mg)under an argon atmosphere, and the mixture was stirred at 70° C.overnight. The reaction solution was cooled to room temperature, waterwas then added thereto, and the mixture was extracted with ethylacetate. The ethyl acetate layer was then washed with water and wasdried over anhydrous sodium sulfate. The solvent was removed bydistillation under the reduced pressure, and the residue was purified bythin layer chromatography using hexane-acetone to give the titlecompound (5.2 mg, yield 12%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.73 (s, 3H), 4.06 (s, 3H), 4.08 (s, 3H),6.41 (d, J=5.4 Hz, 1H), 7.31 (d, J=8.5 Hz, 1H), 7.36 (d, J=3.2 Hz, 1H),7.51 (d, J=8.5 Hz, 1H), 7.53 (s, 1H), 7.70 (s, 1H), 7.79 (d, J=3.2 Hz,1H), 8.44 (d, J=5.4 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 380 (M+1)⁺

Compound 2604-[2-(4,5-Dimethylthiazol-2-yl)-5,6-dimethyl-pyridin-3-yloxy]-6,7-dimethoxy-quinoline

4,5-Dimethylthiazole (1.0 g) was dissolved in tetrahydrofuran (40 ml)under an argon atmosphere to prepare a solution. A 1.6M hexane solution(5.6 ml) of n-butyllithium was added dropwise at −78° C., and themixture was then stirred at −78° C. for 30 min. A solution of4,5-dimethylfurfural (1 g) in tetrahydrofuran (20 ml) was added dropwisethereto, and the temperature of the mixture was raised to roomtemperature with stirring. Water was added to the reaction solution tostop the reaction. The solvent was removed by distillation under thereduced pressure, water was added to the residue, and the mixture wasextracted with ethyl acetate. The ethyl acetate layer was then washedwith water and was dried over anhydrous sodium sulfate. The solvent wasremoved by distillation under the reduced pressure, and the residue waspurified by column chromatography using hexane-acetone to give(4,5-dimethylfuran-2-yl)-(4,5-dimethylthiazol-2-yl)-methanol (945 mg,yield 50%).

(4,5-Dimethylfuran-2-yl)-(4,5-dimethylthiazol-2-yl)-methanol (945 mg)was dissolved in chloroform (20 ml) to prepare a solution. Manganesedioxide (3.5 g) was added to the solution, and the mixture was stirredat room temperature overnight. The reaction solution was filteredthrough Celite, and the solvent was removed from the filtrate bydistillation under the reduced pressure to give(4,5-dimethylfuran-2-yl)-(4,5-dimethylthiazol-2-yl)-methanone (910 mg,yield 97%).

(4,5-Dimethylfuran-2-yl)-(4,5-dimethylthiazol-2-yl)-methanone (910 mg),methanol (7 ml), and 8 ml of a 28% aqueous ammonia solution were placedin a sealed tube, and the mixture was stirred at 160° C. overnight. Thereaction solution was cooled to room temperature, the solvent was thenremoved by distillation under the reduced pressure, and the residue waspurified by column chromatography using hexane-ethyl acetate to give5,6-dimethyl-2-(4,5-dimethylthiazol-2-yl)-pyridin-3-ol (782 mg, yield86%).

Dimethyl sulfoxide (2 ml) was added to5,6-dimethyl-2-(4,5-dimethylthiazol-2-yl)-pyridin-3-ol (50 mg),4-chloro-6,7-dimethoxyquinoline (143 mg), cesium carbonate (209 mg), and4-(N,N-dimethylamino)-pyridine (78 mg), and the mixture was stirred at140° C. overnight. The reaction solution was cooled to room temperature,water was then added to the cooled solution, and the mixture wasextracted with ethyl acetate. The ethyl acetate layer was then washedwith water and was dried over anhydrous sodium sulfate. The solvent wasremoved by distillation under the reduced pressure, and the residue waspurified by thin layer chromatography using hexane-acetone to give thetitle compound (7.7 mg, yield 90%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.13 (s, 3H), 2.27 (s, 3H), 2.35 (s, 3H),2.64 (s, 3H), 4.07 (s, 3H), 4.07 (s, 3H), 6.33 (d, J=5.1 Hz, 1H), 7.33(s, 1H), 7.45 (s, 1H), 7.71 (s, 1H), 8.42 (d, J=5.4 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 444 (M+Na)⁺

Compound 2613-(6,7-Dimethoxy-quinolin-4-yloxy)-6-methyl-[2,2′]-bipyridine

N,N-Dimethylformamide (1.2 ml) was added to4-(2-iodo-6-methyl-pyridin-3-yloxy)-6,7-dimethoxy-quinoline (compound116) (50 mg), tetrakistriphenylphosphine palladium (14 mg),tri-n-butyl-(2-pyridyl)-tin (65 mg), and cesium fluoride (36 mg) underan argon atmosphere, and the mixture was stirred at 70° C. for threenights. The reaction solution was cooled to room temperature, water wasthen added thereto, and the mixture was extracted with ethyl acetate.The ethyl acetate layer was then washed with water and was dried overanhydrous sodium sulfate.

Likewise, N,N-dimethylformamide (1.2 ml) was added to4-(2-iodo-6-methyl-pyridin-3-yloxy)-6,7-dimethoxy-quinoline (compound116) (50 mg), tris(dibenzylideneacetone) (chloroform)dipalladium(0) (6.1mg), (±)-2,2″-(diphenylphosphino)-binaphthyl (3.7 mg),tri-n-butyl-(2-pyridyl)-tin (65 mg), and cesium fluoride (36 mg) underan argon atmosphere, and the mixture was stirred at 70° C. for 3 nights.The reaction solution was cooled to room temperature, water was thenadded thereto, and the mixture was extracted with ethyl acetate. Theethyl acetate layer was then washed with water and was dried overanhydrous sodium sulfate.

The above two ethyl acetate layers were combined, and the solvent wasremoved by distillation under the reduced pressure. The residue waspurified by thin layer chromatography using ether-methanol to give thetitle compound (14 mg, yield 32%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.72 (s, 3H), 4.02 (s, 3H), 4.03 (s, 3H),6.37 (d, J=5.4 Hz, 1H), 7.13 (dd, J=4.9, 7.3 Hz, 1H), 7.31 (d, J=8.5 Hz,1H), 7.40 (s, 1H), 7.52 (d, J=8.5 Hz, 1H), 7.53 (s, 1H), 7.55-7.63 (m,1H), 7.79 (d, J=7.8 Hz, 1H), 8.39 (d, J=5.4 Hz, 1H), 8.50 (d, J=4.6 Hz,1H)

Mass spectrometric value (ESI−MS, m/z): 374 (M+1)⁺

Compound 2623-(6,7-Dimethoxy-quinolin-4-yloxy)-6-methyl-[2,3′]bipyridine

N,N-Dimethylformamide (1 ml), ethanol (0.5 ml), and a 2 M aqueouspotassium carbonate solution (1 ml) were added to4-(2-iodo-6-methyl-pyridin-3-yloxy)-6,7-dimethoxy-quinoline (compound116) (50 mg), tetrakistriphenylphosphine palladium (14 mg), and3-pyridylboronic acid (44 mg) under an argon atmosphere, and the mixturewas stirred at 70° C. for 3 hr. The reaction solution was cooled to roomtemperature, water was then added to the reaction solution, and themixture was extracted with ethyl acetate. The ethyl acetate layer wasthen washed with water and was dried over anhydrous sodium sulfate. Thesolvent was removed by distillation under the reduced pressure, and theresidue was purified by thin layer chromatography usingchloroform-methanol to give the title compound (33 mg, yield 75%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.71 (s, 3H), 4.05 (s, 3H), 4.06 (s, 3H),6.40 (d, J=5.4 Hz, 1H), 7.22-7.32 (m, 2H), 7.46-7.57 (m, 3H), 8.16 (d,J=8.0 Hz, 1H), 8.44 (d, J=5.4 Hz, 1H), 8.52 (dd, J=3.2, 1.5 Hz, 1H),9.06 (s, 1H)

Mass spectrometric value (ESI−MS, m/z): 374 (M+1)⁺

Compound 2633-(6,7-Dimethoxy-quinolin-4-yloxy)-6-methyl-[2,4′]bipyridine

N,N-Dimethylformamide (1 ml), ethanol (0.5 ml), and a 2 M aqueouspotassium carbonate solution (1 ml) were added to4-(2-iodo-6-methyl-pyridin-3-yloxy)-6,7-dimethoxy-quinoline (compound116) (50 mg), tetrakistriphenylphosphine palladium (14 mg) and4-pyridylboronic acid (44 mg) under an argon atmosphere, and the mixturewas stirred at 70° C. for 3 hr. The reaction solution was cooled to roomtemperature, water was then added to the reaction solution, and themixture was extracted with ethyl acetate. The ethyl acetate layer wasthen washed with water and was dried over anhydrous sodium sulfate. Thesolvent was removed by distillation under the reduced pressure, and theresidue was purified by thin layer chromatography usingchloroform-methanol to give the title compound (29 mg, yield 66%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.71 (s, 3H), 4.04 (s, 3H), 4.07 (s, 3H),6.42 (d, J=5.4 Hz, 1H), 7.33 (d, J=8.3 Hz, 1H), 7.49 (d, J=8.3 Hz, 1H),7.49 (s, 1H), 7.55 (s, 1H), 7.79 (d, J=6.1 Hz, 2H), 8.46 (d, J=5.4 Hz,1H), 8.58 (d, J=6.1 Hz, 2H)

Mass spectrometric value (ESI−MS, m/z): 374 (M+1)⁺

Compound 2643-(6,7-Dimethoxy-quinolin-4-yloxy)-6,6′-dimethyl-[2,2′]bipyridine

2-Bromo-6-methylpyridine (191 mg) was dissolved in tetrahydrofuran (5ml) to prepare a solution which was then cooled to −78° C. A 1.57 Mn-butyllithium/hexane solution (1 ml) was added to the reactionsolution, and the mixture was stirred at −78° C. for 10 min. Tributyltinchloride (0.4 ml) was added to the reaction solution, and the mixturewas stirred at room temperature for one hr. Water was then added to thereaction solution, and the mixture was extracted with ethyl acetate. Theethyl acetate layer was then washed with water and was dried overanhydrous sodium sulfate. The solvent was removed by distillation underthe reduced pressure, and the residue was used in the next reactionwithout purification.

The residue, 4-(2-iodo-6-methyl-pyridin-3-yloxy)-6,7-dimethoxy-quinoline(compound 116) (205 mg), and tetrakistriphenylphosphine palladium (48mg) were dissolved in N,N-dimethylformamide (25 ml), copper(II) oxide(28 mg) was added to the solution, and the mixture was stirred at 100°C. overnight. The reaction solution was cooled to room temperature,water was then added to the reaction solution, and the mixture wasextracted with ethyl acetate. The ethyl acetate layer was then washedwith water and was dried over anhydrous sodium sulfate, the solvent wasremoved by distillation under the reduced pressure, and the residue waspurified by thin layer chromatography using acetone-chloroform to givethe title compound (11 mg, yield 6%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.22 (s, 3H), 2.71 (s, 3H), 4.03 (s, 3H),4.03 (s, 3H), 6.32 (d, J=5.1 Hz, 1H), 6.95 (d, J=7.6 Hz, 1H), 7.31 (d,J=8.1 Hz, 1H), 7.37 (s, 1H), 7.49 (dd, J=7.6, 7.8 Hz, 1H), 7.54 (d,J=8.3 Hz, 1H), 7.55 (s, 1H), 7.63 (d, J=7.3 Hz, 1H), 8.36 (d, J=5.2 Hz,1H)

Mass spectrometric value (ESI−MS, m/z): 410 (M+Na)⁺

Compound 2656,7-Dimethoxy-4-(6-methyl-2-pyrimidin-5-yl-pyridin-3-yloxy)-quinoline

N,N-Dimethylformamide (1 ml) and a 2 M aqueous potassium carbonatesolution (1 ml) were added to4-(2-iodo-6-methyl-pyridin-3-yloxy)-6,7-dimethoxy-quinoline (compound116) (50 mg), tetrakistriphenylphosphine palladium (14 mg), and5-piperidylboronic acid (44 mg) under an argon atmosphere, and themixture was stirred at 70° C. for 5 hr. The reaction solution was cooledto room temperature, water was then added to the reaction solution, andthe mixture was extracted with ethyl acetate. The ethyl acetate layerwas then washed with water and was dried over anhydrous sodium sulfate.The solvent was removed by distillation under the reduced pressure, andthe residue was purified by thin layer chromatography usingchloroform-methanol to give the title compound (38 mg, yield 86%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.70 (s, 3H), 4.03 (s, 3H), 4.05 (s, 3H),6.39 (d, J=5.1 Hz, 1H), 7.31 (d, J=8.3 Hz, 1H), 7.43 (s, 1H), 7.46 (s,1H), 7.48 (d, J=8.3 Hz, 1H), 8.47 (d, J=5.4 Hz, 1H), 9.14 (s, 1H), 9.30(s, 2H)

Mass spectrometric value (ESI−MS, m/z): 397 (M+Na)⁺

Compound 2663-(6,7-Dimethoxy-quinolin-4-yloxy)-6-methylsulfanyl-[2,2′]bipyridine

6-Fluoro-2-iodo-pyridin-3-ol (50 mg) was dissolved in acetonitrile (2ml) to prepare a solution. Methyl iodide (148 mg) and potassiumcarbonate (87 mg) were added to the solution, and the mixture wasstirred at room temperature overnight. The solvent was removed bydistillation under the reduced pressure, water was then added to theresidue, and the mixture was extracted with chloroform. The chloroformlayer was washed with water and was dried over anhydrous magnesiumsulfate, the solvent was removed by distillation under the reducedpressure, and the residue was purified by thin layer chromatographyusing chloroform to give 6-fluoro-2-iodo-3-methoxypyridine (52 mg, yield100%).

6-Fluoro-2-iodo-3-methoxypyridine (84 mg), tetrakistriphenylphosphinepalladium (0) (38 mg), and copper(II) oxide (53 mg) were suspended inN,N-dimethylformamide (2 ml). 2-Tributylstannylpyridine (244 mg) wasadded to the suspension, and the mixture was stirred at 100° C.overnight. The reaction solution was cooled to room temperature. Thereaction solution was then filtered, the solvent was removed from thefiltrate by distillation under the reduced pressure. Water was thenadded to the residue, and the mixture was extracted withdichloromethane. The dichloromethane layer was washed with water andsaturated brine and was dried over anhydrous magnesium sulfate. Thesolvent was removed by distillation under the reduced pressure, and theresidue was purified by thin layer chromatography usingchloroform-methanol to give 6-fluoro-3-methoxy-[2,2′]bipyridine (12 mg,yield 18%).

6-Fluoro-3-methoxy-[2,2′]bipyridine (12 mg) and sodium thiomethoxide (41mg) were suspended in N,N-dimethylformamide (1.5 ml), and the suspensionwas stirred at 160° C. overnight. The reaction solution was cooled toroom temperature, the reaction solution was then filtered, and thesolvent was removed from the filtrate by distillation under the reducedpressure. The residue was purified by thin layer chromatography usingacetone-chloroform to give 6-methylsulfanyl-[2,2′]bipyridin-3-ol (6 mg,yield 47%).

6-Methylsulfanyl-[2,2′]bipyridin-3-ol (6 mg),4-chloro-6,7-dimethoxyquinoline (18 mg), 4-dimethylaminopyridine (10mg), and cesium carbonate (27 mg) were suspended in N,N-dimethylsulfoxide (1 ml), and the suspension was stirred at 140° C. overnight.The reaction solution was cooled to room temperature, water was thenadded to the reaction solution, and the mixture was extracted with ethylacetate. The ethyl acetate layer was then washed with water andsaturated brine and was dried over anhydrous magnesium sulfate. Thesolvent was removed by distillation under the reduced pressure, and theresidue was purified by thin layer chromatography using acetone-hexaneto give the title compound (1 mg, yield 8%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.61 (s, 3H), 3.96 (s, 6H), 6.27 (d, J=5.6Hz, 1H), 7.05 (m, 1H), 7.26 (d, J=8.4 Hz, 1H), 7.31 (s, 1H), 7.41 (d,J=8.4 Hz, 1H), 7.52 (s, 1H), 7.59 (dd, J=8.0, 1.6 Hz, 1H), 7.86 (d,J=7.6 Hz, 1H), 8.27 (d, J=7.6 Hz, 1H), 8.31 (d, J=5.6 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 428 (M+Na)⁺

Compound 2673-(6,7-Dimethoxy-quinolin-4-yloxy)-6-methylsulfanyl-[2,3′]bipyridine

6-Fluoro-2-iodo-3-methoxypyridine (52 mg), tetrakistriphenylphosphinepalladium(0) (24 mg), and 3-pyridineboronic acid (76 mg) were suspendedin a mixed solvent composed of N,N-dimethylformamide (0.75 ml) and a 2 Naqueous potassium carbonate solution (0.75 ml), and the suspension wasstirred at 80° C. for 4 hr. The reaction solution was cooled to roomtemperature, the reaction solution was then filtered, and the solventwas removed from the filtrate by distillation under the reducedpressure. Water was then added to the residue, and the mixture wasextracted with dichloromethane. The dichloromethane layer was washedwith water and saturated brine and was dried over anhydrous magnesiumsulfate. The solvent was removed by distillation under the reducedpressure, and the residue was purified by thin layer chromatographyusing acetone-chloroform to give 6-fluoro-3-methoxy-[2,3′]bipyridine (31mg, yield 72%).

6-Fluoro-3-methoxy-[2,3′]bipyridine (30 mg) and sodium thiomethoxide(103 mg) were suspended in N,N-dimethylformamide (1.5 ml), and thesuspension was stirred at 160° C. for 4 hr. The reaction solution wascooled to room temperature, the reaction solution was filtered, and thesolvent was removed from the filtrate by distillation under the reducedpressure. The residue was purified by thin layer chromatography usingchloroform-methanol to give 6-methylsulfanyl-[2,3′]bipyridin-3-ol (13mg, yield 45%).

6-Methylsulfanyl-[2,3′]bipyridin-3-ol (13 mg),4-chloro-6,7-dimethoxyquinoline (46 mg), and 4-dimethylaminopyridine (29mg) were suspended in o-dichlorobenzene (2 ml), and the suspension wasstirred at 140° C. for 4 hr. The reaction solution was cooled to roomtemperature, water was then added to the reaction solution, and themixture was extracted with ethyl acetate. The ethyl acetate layer wasthen washed with water and saturated brine and was dried over anhydrousmagnesium sulfate. The solvent was removed by distillation under thereduced pressure, and the residue was purified by thin layerchromatography using acetone-chloroform to give the title compound (25mg, yield 91%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.61 (s, 3H), 3.96 (s, 6H), 6.32 (d, J=5.2Hz, 1H), 7.15-7.25 (m, 2H), 7.30-7.37 (m, 2H), 7.43 (s, 1H), 8.17 (m,1H), 8.37 (d, J=5.2 Hz, 1H), 8.46 (m, 1H), 9.17 (s, 1H)

Mass spectrometric value (ESI−MS, m/z): 428 (M+Na)⁺

Compound 2684-(5,6-Dimethyl-2-phenyl-pyridin-3-yloxy)-6,7-dimethoxy-quinoline

Carbon disulfide (35 ml) was added to benzoyl chloride (7.3 g) andanhydrous aluminum chloride (7.0 g) under an argon atmosphere, and asolution of 2,3-dimethylfuran (5.0 g) in carbon disulfide (35 ml) wasadded dropwise thereto at 10° C. The mixture was then stirred for 30 minwhile raising the temperature to room temperature. 10% Hydrochloric acid(200 ml) was added to the reaction solution, and the mixture wasextracted with dichloromethane. The dichloromethane layer was thenwashed with water and a 5% aqueous sodium bicarbonate solution and wasdried over anhydrous sodium sulfate. The solvent was removed bydistillation under the reduced pressure, and the residue was purified bycolumn chromatography using hexane-ethyl acetate to give(4,5-dimethylfuran-2-yl)-phenyl-methanone (2.5 g, yield 25%).

(4,5-Dimethylfuran-2-yl)-phenyl-methanone (1 g) and ammonium acetate(910 mg) were placed in a sealed tube, and the mixture was stirred at250° C. for 10 hr. The reaction solution was cooled to room temperature,the solvent was then removed by distillation under the reduced pressure,and the residue was purified by column chromatography using hexane-ethylacetate to give 5,6-dimethyl-2-phenyl-pyridin-3-ol (160 g, yield 16%).

1,2-Dichlorobenzene (4.5 ml) was added to5,6-dimethyl-2-phenyl-pyridin-3-ol (267 mg),4-chloro-6,7-dimethoxyquinoline (100 mg), and4-(N,N-dimethylamino)-pyridine (164 mg), and the mixture was stirred at140° C. for 8 hr. The reaction solution was cooled to room temperature,and the solvent was then removed by distillation under the reducedpressure. Water was added to the residue, and the mixture was extractedwith chloroform. The chloroform layer was washed with water and wasdried over anhydrous sodium sulfate. The solvent was removed bydistillation under the reduced pressure, and the residue was purified bythin layer chromatography using hexane-acetone to give the titlecompound (159 mg, yield 92%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.40 (s, 3H), 2.67 (s, 3H), 4.07 (s, 3H),4.09 (s, 3H), 6.43 (d, J=5.1 Hz, 1H), 7.28-7.36 (m, 4H), 7.46 (s, 1H),7.55 (s, 1H), 7.89 (dd, J=3.2, 6.4 Hz, 2H), 8.41 (d, J=5.1 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 409 (M+Na)⁺

Compound 2693-(6,7-Dimethoxy-quinolin-4-yloxy)-5,6-dimethyl-[2,2′]bipyridine

2,3-Dimethylfuran (5 g) was dissolved in diethyl ether (75 ml) under anargon atmosphere. A 1.6 M hexane solution (35.7 ml) of n-butyllithiumwas added dropwise thereto at 0° C., and the mixture was stirred underreflux for 2.5 hr. Thereafter, the reaction solution was cooled to −78°C., a solution of 2-cyanopyridine (6.0 g) in diethyl ether (20 ml) wasadded dropwise thereto, and the mixture was stirred at room temperaturefor 3 hr. The reaction solution was poured into ice to stop thereaction. The reaction solution was adjusted to pH 5 by the addition of2 M hydrochloric acid and was then extracted with chloroform. Thechloroform layer was then washed with water and was dried over anhydroussodium sulfate. The solvent was removed by distillation under thereduced pressure, and the residue was purified by column chromatographyusing hexane-ethyl acetate to give(4,5-dimethylfuran-2-yl)-(2-pyridyl)-methanone (1.8 g, yield 17%).

(4,5-Dimethylfuran-2-yl)-(2-pyridyl)-methanone (1.6 g), methanol (15ml), and a 28% aqueous ammonia solution (15 ml) were placed in a sealedtube, and the mixture was stirred at 160° C. overnight. The reactionsolution was cooled to room temperature, the solvent was then removed bydistillation under the reduced pressure, and the residue was purified bycolumn chromatography using hexane-ethyl acetate to give5,6-dimethyl-[2,2′]-bipyridin-3-ol (1.2 g, yield 75%).

Dimethyl sulfoxide (1.5 ml) was added to5,6-dimethyl-[2,2′]-bipyridin-3-ol (30 mg),4-chloro-6,7-dimethoxyquinoline (101 mg), and cesium carbonate (147 mg),and the mixture was stirred at 130° C. for 7 hr. The reaction solutionwas cooled to room temperature, water was then added to the reactionsolution, and the mixture was extracted with ethyl acetate. The ethylacetate layer was then washed with water and was dried over anhydroussodium sulfate. The solvent was removed by distillation under thereduced pressure, and the residue was purified by thin layerchromatography using hexane-acetone to give the title compound (12 mg,yield 20%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.37 (s, 3H), 2.65 (s, 3H), 4.02 (s, 3H),4.02 (s, 3H), 6.36 (d, J=5.4 Hz, 1H), 7.10 (dd, J=5.6, 7.3 Hz, 1H), 7.35(s, 1H), 7.37 (s, 1H), 7.53 (s, 1H), 7.57 (ddd, J=1.7, 1.7, 7.8 Hz, 1H),7.78 (d, J=7.8 Hz, 1H), 8.39 (d, J=5.4 Hz, 1H), 8.51 (d, J=4.1 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 410 (M+Na)⁺

Compound 2703-(6,7-Dimethoxy-quinolin-4-yloxy)-5,6-dimethyl-[2,3′]bipyridine

2,3-Dimethylfuran (5 g) was dissolved in diethyl ether (75 ml) under anargon atmosphere, a 1.6 M hexane solution (35.7 ml) of n-butyllithiumwas added dropwise thereto at 0° C., and the mixture was stirred underreflux for 2.5 hr. Thereafter, the reaction solution was cooled to −78°C., a solution of 3-cyanopyridine (6.0 g) in diethyl ether (20 ml) wasadded dropwise thereto, and the mixture was stirred at room temperaturefor 3 hr. The reaction solution was poured into ice to stop the reactionsolution. The reaction solution was adjusted to pH 5 by the addition of2 M hydrochloric acid and was extracted with chloroform. The chloroformlayer was then washed with water and was dried over anhydrous sodiumsulfate. The solvent was removed by distillation under the reducedpressure, and the residue was purified by column chromatography usinghexane-ethyl acetate to give(4,5-dimethylfuran-2-yl)-(3-pyridyl)-methanone (1.9 g, yield 18%).

(4,5-Dimethylfuran-2-yl)-(3-pyridyl)-methanone (1.8 g), methanol (30ml), and a 28% aqueous ammonia solution (30 ml) were placed in a sealedtube and were stirred at 160° C. overnight. The reaction solution wascooled to room temperature, and the solvent was then removed bydistillation under the reduced pressure. The residue was purified bycolumn chromatography using hexane-ethyl acetate to give5,6-dimethyl-[2,3′]-bipyridin-3-ol (1.1 g, yield 63%).

5,6-Dimethyl-[2,3′]-bipyridin-3-ol (50 mg),4-chloro-6,7-dimethoxyquinoline (168 mg), and4-(N,N-dimethylamino)-pyridine (92 mg) were dissolved in1,2-dichlorobenzene (2.5 ml), and the mixture was stirred at 140° C.overnight. The reaction solution was cooled to room temperature, and thesolvent was then removed by distillation under the reduced pressure. Theresidue was purified by thin layer chromatography using hexane-acetoneto give the title compound (81 mg, yield 84%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.35 (s, 3H), 2.61 (s, 3H), 4.01 (s, 3H),4.02 (s, 3H), 6.36 (d, J=5.4 Hz, 1H), 7.22 (dd, J=4.6, 7.8 Hz, 1H), 7.30(s, 1H), 7.39 (s, 1H), 7.47 (s, 1H), 8.16 (ddd, J=2.0, 2.0, 8.0 Hz, 1H),8.43 (d, J=5.1 Hz, 1H), 8.48 (dd, J=1.5, 4.9 Hz, 1H), 9.13 (d, J=1.7 Hz,1H)

Mass spectrometric value (ESI−MS, m/z): 410 (M+Na)⁺

Compound 2713-(6,7-Dimethoxy-quinolin-4-yloxy)-5,6,6′-trimethyl-[2,2′]bipyridine

2-Bromo-6-picoline (1.5 g) was dissolved in tetrahydrofuran (40 ml)under an argon atmosphere to prepare a solution. A 1.6 M hexane solution(5.6 ml) of n-butyllithium was added dropwise to the solution at −78°C., and the mixture was then stirred at −78° C. for 30 min. A solutionof 4,5-dimethylfurfural (1 g) in tetrahydrofuran (20 ml) was addeddropwise thereto, and the temperature of the mixture was raised to roomtemperature while stirring. Water was added to the reaction solution tostop the reaction, and the solvent was removed by distillation under thereduced pressure. Water was added to the residue, and the mixture wasextracted with ethyl acetate. The ethyl acetate layer was then washedwith water and was dried over anhydrous sodium sulfate. The solvent wasremoved by distillation under the reduced pressure, and the residue waspurified by column chromatography using hexane-acetone to give(4,5-dimethylfuran-2-yl)-(6-methyl-pyridin-2-yl)-methanol (1.4 g, yield74%).

(4,5-Dimethylfuran-2-yl)-(6-methyl-pyridin-2-yl)-methanol (1.4 g) wasdissolved in chloroform (30 ml) to prepare a solution. Manganese dioxide(5.7 g) was added to the solution, and the mixture was stirred at roomtemperature overnight. Further, manganese dioxide (1.8 g) was then addedthereto, and the mixture was stirred overnight. The reaction solutionwas filtered through Celite. The solvent was removed from the filtrateby distillation under the reduced pressure to give(4,5-dimethylfuran-2-yl)-(6-methyl-pyridin-2-yl)-methanone (815 mg,yield 58%).

(4,5-Dimethylfuran-2-yl)-(6-methyl-pyridin-2-yl)-methanone (810 mg),methanol (7 ml), and a 28% aqueous ammonia solution (7 ml) were placedin a sealed tube, and the mixture was stirred at 160° C. overnight. Thereaction solution was cooled to room temperature, the solvent was thenremoved by distillation under the reduced pressure, and the residue waspurified by column chromatography using hexane-ethyl acetate to give5,6,6′-trimethyl-[2,2′]bipyridin-3-ol (753 mg, yield 93%).

Dimethyl sulfoxide (2 ml) was added to5,6,6″-trimethyl-[2,2′]bipyridin-3-ol (50 mg),4-chloro-6,7-dimethoxyquinoline (157 mg), cesium carbonate (229 mg), and4-(N,N-dimethylamino)-pyridine (86 mg), and the mixture was stirred at140° C. overnight. The reaction solution was cooled to room temperature,water was then added to the reaction solution, and the mixture wasextracted with ethyl acetate. The ethyl acetate layer was then washedwith water and was dried over anhydrous sodium sulfate. The solvent wasremoved by distillation under the reduced pressure, and the residue waspurified by thin layer chromatography using hexane-acetone to give thetitle compound (17 mg, yield 18%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.21 (s, 3H), 2.38 (s, 3H), 2.64 (s, 3H),4.03 (s, 6H), 6.32 (d, J=5.4 Hz, 1H), 6.93 (d, J=7.6 Hz, 1H), 7.38 (s,2H), 7.47 (t, J=5.9 Hz, 1H), 7.57 (s, 1H), 7.63 (d, J=7.8 Hz, 1H), 8.36(d, J=5.4 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 402 (M+1)⁺

Compound 2723-(6,7-Dimethoxy-quinolin-4-yloxy)-5,6,5′-trimethyl-[2,2′]bipyridine

2-Bromo-5-picoline (1.5 g) was dissolved in tetrahydrofuran (40 ml)under an argon atmosphere to prepare a solution. A 1.6 M hexane solution(5.6 ml) of n-butyllithium was added dropwise to the solution at −78° C.The reaction solution was then stirred at −78° C. for 30 min. A solutionof 4,5-dimethylfurfural (1 g) in tetrahydrofuran (20 ml) was addeddropwise thereto, and the temperature of the mixture was raise to roomtemperature with stirring. Water was added to the reaction solution tostop the reaction. The solvent was removed by distillation under thereduced pressure, water was added to the residue, and the mixture wasextracted with ethyl acetate. The ethyl acetate layer was then washedwith water and was dried over anhydrous sodium sulfate. The solvent wasremoved by distillation under the reduced pressure, and the residue waspurified by column chromatography using hexane-ethyl acetate to give(4,5-dimethylfuran-2-yl)-(5-methyl-pyridin-2-yl)-methanol (855 mg, yield44%).

(4,5-Dimethylfuran-2-yl)-(5-methyl-pyridin-2-yl)-methanol (850 mg) wasdissolved in chloroform (40 ml) to prepare a solution. Manganese dioxide(3.4 g) was added to the solution, and the mixture was stirred at roomtemperature overnight. The reaction solution was filtered throughCelite. The solvent was removed from the filtrate by distillation underthe reduced pressure, and the residue was purified by columnchromatography using hexane-ethyl acetate to give(4,5-dimethylfuran-2-yl)-(5-methyl-pyridin-2-yl)-methanone (788 mg,yield 93%).

(4,5-Dimethylfuran-2-yl)-(6-methyl-pyridin-2-yl)-methanone (780 mg),methanol (7 ml), and a 28% aqueous ammonia solution (7 ml) were placedin a sealed tube and were stirred at 160° C. overnight. The reactionsolution was cooled to room temperature, the solvent was then removed bydistillation under the reduced pressure, and the residue was purified bycolumn chromatography using hexane-ethyl acetate to give5,6,5′-trimethyl-[2,2′]bipyridin-3-ol (529 mg, yield 68%).

Dimethyl sulfoxide (2.8 ml) was added to5,6,5′-trimethyl-[2,2′]bipyridin-3-ol (60 mg),4-chloro-6,7-dimethoxyquinoline (184 mg), cesium carbonate (274 mg),4-(N,N-dimethylamino)-pyridine (51 mg), and cesium fluoride (64 mg) toprepare a solution which was then stirred at 140° C. overnight. Thereaction solution was cooled to room temperature, water was then addedto the reaction solution, and the mixture was extracted with ethylacetate. The ethyl acetate layer was then washed with water and wasdried over anhydrous sodium sulfate. The solvent was removed bydistillation under the reduced pressure, and the residue was purified bythin layer chromatography using chloroform-methanol to give the titlecompound (33 mg, yield 29%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.24 (s, 3H), 2.37 (s, 3H), 2.65 (s, 3H),4.04 (s, 6H), 6.35 (d, J=5.4 Hz, 1H), 7.34 (s, 1H), 7.36-7.41 (m, 2H),7.56 (s, 1H), 7.70 (d, J=8.1 Hz, 1H), 8.36 (d, J=2.2 Hz, 1H), 8.39 (d,J=5.1 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 424 (M+Na)⁺

Compound 2733-(6,7-Dimethoxy-quinolin-4-yloxy)-5,6,4′-trimethyl-[2,2′]bipyridine

2-Bromo-4-picoline (1.5 g) was dissolved in tetrahydrofuran (40 ml)under an argon atmosphere to prepare a solution. A 1.6 M hexane solution(5.6 ml) of n-butyllithium was added dropwise to the solution at −78°C., and the mixture was then stirred at −78° C. for 30 min. A solutionof 4,5-dimethylfurfural (1 g) in tetrahydrofuran (20 ml) was addeddropwise thereto, and the temperature of the mixture was raised to roomtemperature with stirring. Water was added to the reaction solution tostop the reaction. The solvent was removed by distillation under thereduced pressure. Water was added to the residue, the mixture wasextracted with ethyl acetate, and the ethyl acetate layer was thenwashed with water and was dried over anhydrous sodium sulfate. Thesolvent was removed by distillation under the reduced pressure, and theresidue was purified by column chromatography using hexane-ethyl acetateto give (4,5-dimethylfuran-2-yl)-(4-methyl-pyridin-2-yl)-methanol (904mg, yield 47%).

(4,5-Dimethylfuran-2-yl)-(4-methyl-pyridin-2-yl)-methanol (900 mg) wasdissolved in chloroform (20 ml) to prepare a solution. Manganese dioxide(3.6 g) was added to the solution, and the mixture was stirred at roomtemperature overnight. Further, manganese dioxide (1.8 g) was then addedto the reaction solution, and the mixture was stirred at roomtemperature for 5 hr. The reaction solution was filtered through Celite,and the solvent was removed from the filtrate by distillation under thereduced pressure, and the residue was purified by column chromatographyusing hexane-ethyl acetate to give(4,5-dimethylfuran-2-yl)-(4-methyl-pyridin-2-yl)-methanone (690 mg,yield 77%).

(4,5-Dimethylfuran-2-yl)-(6-methyl-pyridin-2-yl)-methanone (690 mg),methanol (6 ml), and a 28% aqueous ammonia solution (6 ml) were placedin a sealed tube and were stirred at 160° C. overnight. The reactionsolution was cooled to room temperature, the solvent was then removed bydistillation under the reduced pressure, and the residue was purified bycolumn chromatography using hexane-ethyl acetate to give5,6,4′-trimethyl-[2,2′]bipyridin-3-ol (611 mg, yield 89%).

Dimethyl sulfoxide (2 ml) was added to5,6,4′-trimethyl-[2,2′]bipyridin-3-ol (50 mg),4-chloro-6,7-dimethoxyquinoline (157 mg), and cesium carbonate (229 mg),and the mixture was stirred at 130° C. overnight. The reaction solutionwas cooled to room temperature, water was then added to the solution,and the mixture was extracted with ethyl acetate. The ethyl acetatelayer was then washed with water and was dried over anhydrous sodiumsulfate. The solvent was removed by distillation under the reducedpressure, and the residue was purified by thin layer chromatographyusing hexane-acetone to give the title compound (42 mg, yield 45%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.21 (s, 3H), 2.38 (s, 3H), 2.65 (s, 3H),4.03 (s, 3H), 4.04 (s, 3H), 6.33 (d, J=5.4 Hz, 1H), 6.89-6.96 (m, 1H),7.36 (s, 2H), 7.57 (s, 1H), 7.61-7.64 (m, 1H), 8.35 (d, J=5.1 Hz, 1H),8.37 (d, J=5.1 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 402 (M+1)⁺

Compound 2744-(5,6-Dimethyl-2-pyrimidin-2-yl-pyridin-3-yloxy)-6,7-dimethoxy-quinoline

2,3-Dimethylfuran (1.5 g) was dissolved in diethyl ether (20 ml) underan argon atmosphere to prepare a solution. A 1.6 M hexane solution (10.9ml) of n-butyllithium was added dropwise to the solution at 0° C., andthe mixture was stirred under reflux for 2.5 hr. Thereafter, thereaction solution was cooled to −78° C., a solution of 2-cyanopyrimidine(1.8 g) in diethyl ether (8 ml) was added dropwise thereto, and themixture was stirred at room temperature overnight. The reaction solutionwas poured into ice to stop the reaction. The mixture was acidified with1 M hydrochloric acid and was extracted with ethyl acetate. The ethylacetate layer was then washed with water and was dried over anhydroussodium sulfate. The solvent was removed by distillation under thereduced pressure, and the residue was purified by column chromatographyusing chloroform-acetone to give(4,5-dimethylfuran-2-yl)-(2-pyrimidyl)-methanone (226 mg, yield 7%).

(4,5-Dimethylfuran-2-yl)-(2-pyrimidyl)-methanone (220 mg), methanol (2ml), and a 28% aqueous ammonia solution (2 ml) were placed in a sealedtube, and the mixture was stirred at 160° C. overnight. The reactionsolution was cooled to room temperature, the solvent was removed bydistillation under the reduced pressure, and the residue was purified bycolumn chromatography using hexane-acetone to give5,6-dimethyl-2-pyrimidin-2-yl-pyridin-3-ol (129 mg, yield 59%).

Dimethyl sulfoxide (2.5 ml) was added to5,6-dimethyl-2-pyrimidin-2-yl-pyridin-3-ol (50 mg),4-chloro-6,7-dimethoxyquinoline (167 mg), and cesium carbonate (243 mg),and the mixture was stirred at 130° C. overnight. The reaction solutionwas cooled to room temperature, water was then added to the reactionsolution, and the mixture was extracted with ethyl acetate. The ethylacetate layer was then washed with water and was dried over anhydroussodium sulfate. The solvent was removed by distillation under thereduced pressure, and the residue was purified by thin layerchromatography using hexane-acetone to give the title compound (54 mg,yield 55%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.41 (s, 3H), 2.68 (s, 3H), 4.02 (s, 3H),4.03 (s, 3H), 6.40 (d, J=5.2 Hz, 1H), 7.09 (t, J=4.9 Hz, 1H), 7.36 (s,1H), 7.41 (s, 1H), 7.56 (s, 1H), 8.38 (d, J=5.4 Hz, 1H), 8.64 (d, J=4.9Hz, 2H)

Mass spectrometric value (ESI−MS, m/z): 389 (M+1)⁺

Compound 275 6,7-Dimethoxy-4-(quinolin-3-yloxy)-quinoline

4-Chloro-6,7-dimethoxyquinoline (243 mg), 3-hydroxy-quinoline (100 mg),and 4-dimethylaminopyridine (348 mg) were dissolved in o-dichlorobenzene(13 ml) to prepare a solution which was stirred at 140° C. overnight.The reaction solution was cooled to room temperature, water was thenadded to the reaction solution, and the mixture was extracted with ethylacetate. The ethyl acetate layer was then washed with water and wasdried over anhydrous sodium sulfate, the solvent was removed bydistillation under the reduced pressure, and the residue was purified bythin layer chromatography using acetone-chloroform to give the titlecompound (213 mg, yield 93%).

¹H-NMR (CDCl₃, 400 MHz): δ 4.06 (s, 3H), 4.08 (s, 3H), 6.54 (d, J=5.1Hz, 1H), 7.47 (d, J=0.9 Hz, 1H), 7.56 (d, J=1.6 Hz, 1H), 7.61 (m, 1H),7.74 (m, 1H), 7.80 (d, J=8.1 Hz, 1H), 7.88 (m, 1H), 8.18 (d, J=8.7 Hz,1H), 8.53 (dd, J=0.7, 5.1 Hz, 1H), 8.89 (d, J=2.9 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 333 (M+1)⁺

Compound 276 6,7-Dimethoxy-4-(2-methyl-quinolin-3-yloxy)-quinoline

4-Chloro-6,7-dimethoxyquinoline (240 mg),3-hydroxy-2-methyl-quinoline-4-carboxylic acid (232 mg), and4-dimethylaminopyridine (372 mg) were dissolved in o-dichlorobenzene (10ml) to prepare a solution which was stirred at 160° C. overnight. Thereaction solution was cooled to room temperature, water was then addedto the reaction solution, and the mixture was extracted with ethylacetate. The ethyl acetate layer was then washed with water and wasdried over anhydrous sodium sulfate, the solvent was removed bydistillation under the reduced pressure, and the residue was purified bycolumn chromatography using acetone-chloroform to give the titlecompound (37 mg, yield 11%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.67 (s, 3H), 4.07 (s, 3H), 4.08 (s, 3H),6.39 (d, J=5.1 Hz, 1H), 7.48 (s, 1H), 7.54 (m, 1H), 7.59 (d, J=1.7 Hz,1H), 7.70-7.76 (m, 2H), 7.81 (s, 1H), 8.10 (d, J=8.5 Hz, 1H), 8.50 (dd,J=0.7, 5.1 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 347 (M+1)⁺

Compound 277[3-(6,7-Dimethoxy-quinolin-4-yloxy)-quinolin-2-ylmethyl]-diisopropyl-amine

6,7-Dimethoxy-4-(2-methyl-quinolin-3-yloxy)-quinoline (compound 276)(108 mg) was dissolved in tetrahydrofuran (5 ml) to prepare a solution.A lithiumdiisopropylamide/1.8 M heptane-tetrahydrofuran-ethylbenzenesolution (0.3 ml) was added to the solution at −78° C., and the mixturewas stirred for 10 min. N-Bromosuccimide (180 mg) was added to thereaction solution, and the mixture was stirred at room temperature for 5hr. Water was added to the reaction solution, and the mixture wasextracted with ethyl acetate. The ethyl acetate layer was then washedwith water and was dried over anhydrous sodium sulfate. The solvent wasremoved by distillation under the reduced pressure, and the residue waspurified by thin layer chromatography using methanol-chloroform to givethe title compound (23 mg, yield 16%).

¹H-NMR (CDCl₃, 400 MHz): δ 0.91-0.95 (m, 12H), 3.06 (m, 2H), 4.05 (s,3H), 4.06 (s, 3H), 4.10 (s, 2H), 6.48 (d, J=5.4 Hz, 1H), 7.46 (s, 1H),7.54 (m, 1H), 7.61 (s, 1H), 7.70-7.73 (m, 2H), 7.73 (s, 1H), 8.17 (d,J=8.5 Hz, 1H), 8.51 (d, J=5.4 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 446 (M+1)⁺

Compound 2781-[3-(6,7-Dimethoxy-quinolin-4-yloxy)-quinolin-2-yl]-ethanone

A mixture of 2-nitrobenzoyl chloride (500 mg) with4-trimethylsilanyloxy-pent-3-en-2-one (540 mg) was stirred at 140° C.for 5 min. The reaction solution was cooled to room temperature and wasthen purified by column chromatography using acetone-hexane to give3-(2-nitro-benzoyl)-pentane-2,4-dione (143 mg, yield 20%).

3-(2-Nitro-benzoyl)-pentane-2,4-dione (143 mg) was suspended in a 20%aqueous potassium hydroxide solution (10 ml), and the suspension washeated under reflux for 45 min. The reaction solution was cooled to roomtemperature, was then neutralized with a 1 N aqueous hydrochloric acidsolution, and was extracted with chloroform. The chloroform layer waswashed with water and saturated brine and was dried over anhydrousmagnesium sulfate. The solvent was removed by distillation under thereduced pressure. The residue was purified by thin layer chromatographyusing chloroform to give 2-acetyl-3-quinolinol (22 mg, yield 21%).

2-Acetyl-3-quinolinol (22 mg), 4-chloro-6,7-dimethoxyquinoline (54 mg),and 4-dimethylaminopyridine (88 mg) were suspended in o-dichlorobenzene(5 ml), and the suspension was stirred at 130° C. overnight. Thereaction solution was cooled to room temperature, water was then addedto the reaction solution, and the mixture was extracted with ethylacetate. The ethyl acetate layer was then washed with water andsaturated brine and was dried over anhydrous magnesium sulfate. Thesolvent was removed by distillation under the reduced pressure, and theresidue was purified by thin layer chromatography using acetone-hexaneto give the title compound (6 mg, yield 13%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.70 (s, 3H), 3.99 (s, 6H), 6.30 (d, J=5.2Hz, 1H), 7.42 (s, 1H), 7.53-7.66 (m, 2H), 7.76 (m, 2H), 7.90 (s, 1H),8.16 (d, J=9.2 Hz, 1H), 8.41 (d, J=5.2 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 375 (M+1)⁺

Compound 279[3-(6,7-Dimethoxy-quinolin-4-yloxy)-quinolin-2-yl]-phenyl-methanone

Ethyl 3-hydroxy-2-methyl-quinoline-4-carboxylate (2.10 g) was suspendedin o-dichlorobenzene (50 ml), and the mixture was stirred at 150° C.overnight and was further stirred at 160° C. for one day. The reactionsolution was cooled to room temperature, and the solvent was thenremoved by distillation under the reduced pressure. The residue waspurified by column chromatography using methanol-chloroform to give3-hydroxy-2-methyl-quinoline (976 mg, yield 60%).

3-Hydroxy-2-methyl-quinoline (0.46 g) was suspended in xylene (30 ml),zelene dioxide (2.55 g) was added to the suspension, and the mixture wasstirred at 130° C. for 30 min. Water was added to the reaction solution,and the mixture was extracted with ethyl acetate. The ethyl acetatelayer was then washed with water and was dried over anhydrous sodiumsulfate. The solvent was removed by distillation under the reducedpressure, and the residue was purified by column chromatography usingacetone-chloroform to give 3-hydroxy-quinoline-2-carbaldehyde (124 mg,yield 25%).

3-Hydroxy-quinoline-2-carbaldehyde (124 mg) was dissolved intetrahydrofuran (20 ml) to prepare a solution. A phenylmagnesiumbromide/1.04 M tetrahydrofuran solution (4 ml) was added to the solutionunder ice cooling, and the mixture was stirred at room temperature forone hr. Water was added to the reaction solution, the mixture wasextracted with ethyl acetate. The ethyl acetate layer was then washedwith water and was dried over anhydrous sodium sulfate. The solvent wasremoved by distillation under the reduced pressure, and the residue wasused in the next reaction without purification.

The residue was dissolved in chloroform (15 ml), manganese dioxide (2.56g) was added to the solution, and the mixture was stirred at roomtemperature overnight. The reaction solution was filtered, the solventwas removed by distillation under the reduced pressure, and the residuewas purified by column chromatography using ethyl acetate-hexane to give(3-hydroxy-quinolin-2-yl)-phenyl-methanone (28 mg, yield 16%) (2 steps).

(3-Hydroxy-quinolin-2-yl)-phenyl-methanone (27 mg),4-chloro-6,7-dimethoxyquinoline (120 mg), and 4-dimethylaminopyridine(147 mg) were suspended in o-dichlorobenzene (5 ml), and the suspensionwas stirred at 150° C. for 2 hr. The reaction solution was cooled toroom temperature, and the solvent was removed by distillation under thereduced pressure. Water was then added to the residue, and the mixturewas extracted with ethyl acetate. The organic layer was washed withwater and was dried over anhydrous sodium sulfate, the solvent wasremoved by distillation under the reduced pressure, and the residue waspurified by thin layer chromatography using acetone-chloroform to givethe title compound (20 mg, yield 42%).

¹H-NMR (CDCl₃, 400 MHz): δ 3.89 (s, 3H), 4.03 (s, 3H), 6.67 (d, J=5.2Hz, 1H), 7.27 (s, 1H), 7.40 (s, 1H), 7.44 (dd, J=7.8, 7.8 Hz, 2H), 7.58(m, 1H), 7.67 (m, 1H), 7.78 (dd, J=7.1, 7.1 Hz, 1H), 7.82 (d, J=8.0 Hz,1H), 7.92-7.94 (m, 3H), 8.22 (d, J=8.5 Hz, 1H), 8.52 (d, J=5.1 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 437 (M+1)⁺

Compound 2804-(2-Cyclopentyloxy-quinolin-3-yloxy)-6,7-dimethoxy-quinoline

4-Chloro-6,7-dimethoxyquinoline (106 mg), 2,3-dihydroxyquinoline (50mg), and 4-dimethylaminopyridine (124 mg) were suspended ino-dichlorobenzene (5 ml), and the suspension was stirred at 150° C. for8 hr. The reaction solution was cooled to room temperature, water wasthen added thereto, and the mixture was extracted with ethyl acetate.The organic layer was washed with water and was dried over anhydroussodium sulfate. The solvent was removed by distillation under thereduced pressure, and the residue was purified by column chromatographyusing methanol-chloroform to give6,7-dimethoxy-4-(2-hydroxy-quinolin-3-yloxy)-quinoline (40 mg, yield37%).

6,7-Dimethoxy-4-(2-hydroxy-quinolin-3-yloxy)-quinoline (19 mg) wasdissolved in N,N-dimethylformamide (4 ml) to prepare a solution.Potassium carbonate (180 mg) and cyclopentyl bromide (0.1 ml) were addedto the solution, and the mixture was stirred at room temperatureovernight. Water was added to the reaction solution, and the mixture wasextracted with ethyl acetate. The organic layer was washed with waterand was dried over anhydrous sodium sulfate, and the solvent was removedby distillation under the reduced pressure. The residue was purified bycolumn chromatography using acetone-chloroform to give the titlecompound (14 mg, yield 60%).

¹H-NMR (CDCl₃, 400 MHz): δ 1.23-1.86 (m, 8H), 4.07 (s, 3H), 4.07 (s,3H), 5.65 (m, 1H), 6.39 (d, J=5.4 Hz, 1H), 7.43 (m, 1H), 7.46 (s, 1H),7.62 (s, 1H), 7.64 (m, 1H), 7.72 (d, J=7.8 Hz, 1H), 7.85 (s, 1H), 7.88(d, J=8.5 Hz, 1H), 8.46 (d, J=5.4 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 417 (M+1)⁺

Compound 281 4-(2-Bromo-quinolin-3-yloxy)-6,7-dimethoxy-quinoline

2-Aminobenzaldehyde (650 mg) was dissolved in dichloromethane (20 ml) toprepare a solution. Chloroacetyl chloride (728 mg) was added to thesolution, and the mixture was stirred at room temperature overnight.Water was added thereto, and the mixture was extracted withdichloromethane. The dichloromethane layer was washed with water andsaturated brine and was dried over anhydrous sodium sulfate. The solventwas removed by distillation under the reduced pressure, and the residuewas purified by column chromatography using chloroform to give2-chloro-N-(2-formyl-phenyl)-acetamide (1.05 g, yield 99%).

2-Chloro-N-(2-formyl-phenyl)-acetamide (960 mg) was dissolved in a mixedsolvent composed of water (60 ml) and methanol (24 ml) at 100° C. A 10%aqueous potassium hydroxide solution (12 ml) was added dropwise to thesolution and was then heated under reflux for one hr. The reactionsolution was cooled to room temperature, methanol was then removed underthe reduced pressure, and the residue was neutralized with a 1 N aqueoushydrochloric acid solution. The precipitate was collected by filtration,was washed with ethyl acetate, and was dried under the reduced pressureto give 2,3-dihydroxyquinoline (450 mg, yield 26%).

2,3-Dihydroxyquinoline (450 mg), 4-chloro-6,7-dimethoxyquinoline (575mg), and 4-dimethylaminopyridine (472 mg) were suspended ino-dichlorobenzene (12 ml), and the mixture was stirred at 135° C. for5.5 hr. The reaction solution was cooled to room temperature, water wasthen added to the reaction solution, and the mixture was extracted withethyl acetate. The ethyl acetate layer was then washed with water andsaturated brine and was dried over anhydrous magnesium sulfate. Thesolvent was removed by distillation under the reduced pressure. Theresidue was purified by column chromatography using acetone-chloroformto give 3-(6,7-dimethoxy-quinolin-4-yloxy)-quinolin-2-ol (344 mg, yield77%).

3-(6,7-Dimethoxy-quinolin-4-yloxy)-quinolin-2-ol (50 mg), diphosphoruspentaoxide (51 mg), and tetrabutylammonium bromide (69 mg) weresuspended in o-dichlorobenzene (1 ml), and the suspension was stirred at140° C. for 1.5 hr. The reaction solution was cooled to roomtemperature. A 10% aqueous sodium hydrogencarbonate solution was thenadded to the reaction solution, and the mixture was extracted withchloroform. The chloroform layer was then washed with water andsaturated brine and was dried over anhydrous magnesium sulfate. Thesolvent was removed by distillation under the reduced pressure, and theresidue was purified by thin layer chromatography usingchloroform-methanol to give the title compound (5 mg, yield 8%).

¹H-NMR (CDCl₃, 400 MHz): δ 4.05 (s, 6H), 6.44 (d, J=5.2 Hz, 1H), 7.50(s, 1H), 7.54-7.65 (m, 2H), 7.70-7.79 (m, 2H), 7.89 (s, 1H), 8.11 (d,J=8.4 Hz, 1H), 8.51 (d, J=5.2 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 411 (M+1)⁺

Compound 282 4-(2-Iodo-quinolin-3-yloxy)-6,7-dimethoxy-quinoline

3-(6,7-Dimethoxy-quinolin-4-yloxy)-quinolin-2-ol (50 mg), diphosphoruspentaoxide (51 mg), and tetrabutylammonium iodide (80 mg) were suspendedin o-dichlorobenzene (1 ml), and the mixture was stirred at 140° C. for3.5 hr. The reaction solution was cooled to room temperature, a 10%aqueous sodium hydrogencarbonate solution was then added to the reactionsolution, and the mixture was extracted with chloroform. The chloroformlayer was then washed with water and saturated brine and was dried overanhydrous magnesium sulfate. The solvent was removed therefrom bydistillation under the reduced pressure, and the residue was purified bythin layer chromatography using chloroform-methanol to give the titlecompound (1 mg, yield 2%).

¹H-NMR (CDCl₃, 400 MHz): δ 4.03 (s, 6H), 6.43 (d, J=5.2 Hz, 1H),7.50-7.79 (m, 6H), 8.09 (d, J=8.8 Hz, 1H), 8.47 (d, J=5.2 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 459 (M+1)⁺

Compound 283 6,7-Dimethoxy-4-(2-phenyl-quinolin-3-yloxy)-quinoline

4-Chloro-6,7-dimethoxyquinoline (222 mg), 2-phenylquinolin-3-ol (107mg), and 4-dimethylaminopyridine (340 mg) were suspended ino-dichlorobenzene (11 ml), and the suspension was stirred at 145° C. for7 hr. The reaction solution was cooled to room temperature, water wasadded to the reaction solution, and the mixture was extracted with ethylacetate. The organic layer was washed with water and was dried overanhydrous sodium sulfate. The solvent was removed by distillation underthe reduced pressure. The residue was purified by thin layerchromatography using acetone-chloroform to give the title compound (134mg, yield 68%).

¹H-NMR (CDCl₃, 400 MHz): δ 4.02 (s, 3H), 4.05 (s, 3H), 6.47 (d, J=5.1Hz, 1H), 7.32-7.36 (m, 3H), 7.41 (s, 1H), 7.50 (s, 1H), 7.59 (m, 1H),7.76 (m, 1H), 7.80 (d, J=8.1 Hz, 1H), 7.95-7.98 (m, 3H), 8.24 (d, J=8.6Hz, 1H), 8.45 (d, J=5.1 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 409 (M+1)⁺

Compound 284{3-[3-(6,7-Dimethoxy-quinolin-4-yloxy)-quinolin-2-yl]-phenyl}-methanol

4-(2-Bromo-quinolin-3-yloxy)-6,7-dimethoxy-quinoline (compound 281) (50mg), tetrakistriphenylphosphine palladium(0) (14 mg), and(3-hydroxymethylphenyl)boranic acid (55 mg) were suspended in a mixedsolvent composed of N,N-dimethylformamide (1 ml) and a 2 N aqueouspotassium carbonate solution (1 ml), and the suspension was stirred at80° C. for 2.5 hr. The reaction solution was cooled to room temperature,the reaction solution was then filtered, and the solvent was removedfrom the filtrate by distillation under the reduced pressure. Water wasthen added to the residue, and the mixture was extracted with ethylacetate. The ethyl acetate layer was then washed with water andsaturated brine and was dried over anhydrous magnesium sulfate. Thesolvent was removed by distillation under the reduced pressure, and theresidue was purified by thin layer chromatography using acetone-hexaneto give the title compound (54 mg, yield 97%).

¹H-NMR (CDCl₃, 400 MHz): δ 3.86 (s, 3H), 3.95 (s, 3H), 4.56 (s, 2H),6.24 (d, J=5.2 Hz, 1H), 7.16-7.24 (m, 3H), 7.42 (s, 1H), 7.49 (m, 1H),7.68 (m, 2H), 7.80 (d, J=5.2 Hz, 1H), 7.84 (s, 1H), 8.01 (s, 1H), 8.12(m, 2H)

Mass spectrometric value (ESI−MS, m/z): 437 (M−1)⁻

Compound 2854-[2-(4-Fluoro-phenyl)-quinolin-3-yloxy]-6,7-dimethoxy-quinoline

2-Aminobenzaldehyde (118 mg) and 2-bromo-1-(4-fluoro-phenyl)-ethanone(225 mg) were dissolved in methanol (5 ml) to prepare a solution. Sodiumhydroxide (100 mg) and water (5 ml) were added to the solution, and themixture was stirred at room temperature overnight. Dilute hydrochloricacid was added to the reaction solution, and the mixture was extractedwith ethyl acetate. The ethyl acetate layer was then washed with waterand was dried over anhydrous sodium sulfate. The solvent was removed bydistillation under the reduced pressure, and the residue was purified bythin layer chromatography using ethyl acetate-hexane to give2-(4-fluoro-phenyl)-quinolin-3-ol (53 mg, yield 22%).

2-(4-Fluoro-phenyl)-quinolin-3-ol (52 mg),4-chloro-6,7-dimethoxyquinoline (145 mg), and 4-dimethylaminopyridine(214 mg) were suspended in o-dichlorobenzene (6 ml), and the suspensionwas stirred at 145° C. for 5 hr. The reaction solution was cooled toroom temperature, water was then added to the reaction solution, and themixture was extracted with ethyl acetate. The organic layer was washedwith water and was dried over anhydrous sodium sulfate. The solvent wasremoved by distillation under the reduced pressure, and the residue waspurified by thin layer chromatography using acetone-chloroform to givethe title compound (59 mg, yield 64%).

¹H-NMR (CDCl₃, 400 MHz): δ 4.03 (s, 3H), 4.05 (s, 3H), 6.43 (d, J=5.1Hz, 1H), 7.03 (m, 2H), 7.42 (s, 1H), 7.49 (d, J=2.2 Hz, 1H), 7.59 (m,1H), 7.74-7.80 (m, 2H), 7.94 (d, J=2.0 Hz, 1H), 8.00 (m, 2H), 8.21 (d,J=8.6 Hz, 1H), 8.45 (d, J=5.4 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 427 (M+1)⁺

Compound 2864-[2-(2,4-Difluoro-phenyl)-quinolin-3-yloxy]-6,7-dimethoxy-quinoline

2-Aminobenzaldehyde (360 mg) and2-chloro-1-(2,4-difluoro-phenyl)-ethanone (585 mg) were dissolved inmethanol (15 ml) to prepare a solution. Sodium hydroxide (310 mg) andwater (3 ml) were added to the solution, and the mixture was stirred atroom temperature overnight. A dilute hydrochloric acid was added to thereaction solution, and the mixture was extracted with ethyl acetate. Theethyl acetate layer was then washed with water and was dried overanhydrous sodium sulfate. The solvent was removed by distillation underthe reduced pressure, and the residue was purified by columnchromatography using ethyl acetate-hexane to give2-(2,4-difluoro-phenyl)-quinolin-3-ol (237 mg, yield 41%).

2-(2,4-Difluoro-phenyl)-quinolin-3-ol (220 mg),4-chloro-6,7-dimethoxyquinoline (237 mg), and 4-dimethylaminopyridine(380 mg) were suspended in o-dichlorobenzene (10 ml), and the suspensionwas stirred at 145° C. for 8 hr. The reaction solution was cooled toroom temperature, water was then added to the reaction solution, and themixture was extracted with ethyl acetate. The organic layer was washedwith water and was dried over anhydrous sodium sulfate. The solvent wasremoved by distillation under the reduced pressure. The residue waspurified by thin layer chromatography using acetone-chloroform to givethe title compound (104 mg, yield 27%).

¹H-NMR (CDCl₃, 400 MHz): δ 4.00 (s, 3H), 4.04 (s, 3H), 6.54 (d, J=5.4Hz, 1H), 6.79 (m, 1H), 6.92 (m, 1H), 7.40 (s, 1H), 7.46 (s, 1H),7.59-7.65 (m, 2H), 7.75 (m, 1H), 7.79 (d, J=8.3 Hz, 1H), 7.89 (s, 1H),8.21 (d, J=8.5 Hz, 1H), 8.49 (d, J=5.1 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 445 (M+1)⁺

Compound 287 6,7-Dimethoxy-4-(2-pyridin-2-yl-quinolin-3-yloxy)-quinoline

N,N-Dimethylformamide (1 ml) was added to4-(2-bromo-quinolin-3-yloxy)-6,7-dimethoxy-quinoline (35 mg),tetrakistriphenylphosphine palladium (9.8 mg),tri-n-butyl-(2-pyridyl)-tin (63 mg), and copper(II) oxide (14 mg) underan argon atmosphere, and the mixture was stirred at 100° C. overnight.The reaction solution was cooled to room temperature, water was thenadded thereto, and the mixture was extracted with ethyl acetate. Theethyl acetate layer was then washed with water and was dried overanhydrous sodium sulfate. The solvent was removed by distillation underthe reduced pressure, and the residue was purified by columnchromatography using hexane-acetone. The purification product was thendissolved in methanol, and the solution was added dropwise to water. Theprecipitate was collected by filtration to give the title compound (5.1mg, yield 15%).

¹H-NMR (CDCl₃, 400 MHz): δ 4.04 (s, 3H), 4.05 (s, 3H), 6.46 (d, J=5.4Hz, 1H), 7.19 (dd, J=5.9, 5.9 Hz, 1H), 7.43 (s, 1H), 7.60 (s, 1H),7.60-7.77 (m, 2H), 7.78 (dd, J=8.5, 8.5 Hz, 1H), 7.85 (d, J=8.6 Hz, 1H),7.96 (d, J=7.6 Hz, 1H), 8.05 (s, 1H), 8.30 (d, J=8.3 Hz, 1H), 8.31 (d,J=5.4 Hz, 1H), 8.51 (d, J=4.2 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 432 (M+Na)⁺

Compound 288 6,7-Dimethoxy-4-(2-pyridin-3-yl-quinolin-3-yloxy)-quinoline

4-(2-Bromo-quinolin-3-yloxy)-6,7-dimethoxy-quinoline (compound 281) (50mg), tetrakistriphenylphosphine palladium(0) (14 mg), and3-pyridineboronic acid (42 mg) were suspended in a mixed solventcomposed of N,N-dimethylformamide (1 ml) and a 2 N aqueous potassiumcarbonate solution (1 ml), and the mixture was stirred at 80° C. for 3hr. The reaction solution was cooled to room temperature, the reactionsolution was then filtered, and the solvent was removed from thefiltrate by distillation under the reduced pressure. Water was thenadded to the residue, and the mixture was extracted with ethyl acetate.The ethyl acetate layer was then washed with water and saturated brineand was dried over anhydrous magnesium sulfate. The solvent was removedby distillation under the reduced pressure, and the residue was purifiedby thin layer chromatography using acetone-chloroform to give the titlecompound (16 mg, yield 33%).

¹H-NMR (CDCl₃, 400 MHz): δ 3.96 (s, 3H), 3.97 (s, 3H), 6.40 (d, J=5.2Hz, 1H), 7.23 (dd, J=8.0 Hz, 3.2 Hz, 1H), 7.37 (s, 1H), 7.42 (s, 1H),7.55 (m, 1H), 7.73 (m, 2H), 7.90 (s, 1H), 8.17 (d, J=8.4 Hz, 1H), 8.23(d, J=8.4 Hz, 1H), 8.39 (d, J=5.2 Hz, 1H), 8.50 (dd, J=4.8 Hz, 1.6 Hz,1H), 9.20 (d, J=1.6 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 410 (M+1)⁺

Compound 289 6,7-Dimethoxy-4-(2-pyridin-4-yl-quinolin-3-yloxy)-quinoline

4-(2-Bromo-quinolin-3-yloxy)-6,7-dimethoxy-quinoline (compound 281) (50mg), tetrakistriphenylphosphine palladium(0) (14 mg), and4-pyridineboronic acid (42 mg) were suspended in a mixed solventcomposed of N,N-dimethylformamide (1 ml) and a 2 N aqueous potassiumcarbonate solution (1 ml), and the suspension was stirred at 80° C. for2.5 hr. The reaction solution was cooled to room temperature, thereaction solution was then filtered, and the solvent was removed fromthe filtrate by distillation under the reduced pressure. Water was thenadded to the residue, and the mixture was extracted with ethyl acetate.The ethyl acetate layer was then washed with water and saturated brineand was dried over anhydrous magnesium sulfate. The solvent was removedby distillation under the reduced pressure, and the residue was purifiedby thin layer chromatography using acetone-chloroform to give the titlecompound (13 mg, yield 26%).

¹H-NMR (CDCl₃, 400 MHz): δ 3.95 (s, 3H), 3.98 (s, 3H), 6.41 (d, J=5.6Hz, 1H), 7.39 (s, 1H), 7.40 (s, 1H), 7.56 (m, 1H), 7.73 (m, 2H), 7.84(d, J=4.8 Hz, 2H), 7.91 (s, 1H), 8.18 (d, J=8.8 Hz, 1H), 8.41 (d, J=5.6Hz, 1H), 8.56 (d, J=4.8 Hz, 2H)

Mass spectrometric value (ESI−MS, m/z): 432 (M+Na)⁺

Compound 2904-[2-(5-Chloro-4-methyl-thiophen-2-yl)-quinolin-3-yloxy]-6,7-dimethoxy-quinoline

2-Aminobenzaldehyde (184 mg) and2-bromo-1-(4-bromo-5-chloro-thiophen-2-yl)-ethanone (442 mg) weredissolved in methanol (10 ml) to prepare a solution. Sodium hydroxide(210 mg) and water (5 ml) were added to the solution, and the mixturewas stirred at room temperature for 2 days. Dilute hydrochloric acid wasadded to the reaction solution, and the mixture was extracted withchloroform. The organic layer was then washed with water and was driedover anhydrous sodium sulfate. The solvent was removed by distillationunder the reduced pressure, and the residue was used in the nextreaction without further purification.

The residue, 4-chloro-6,7-dimethoxyquinoline (174 mg), and4-dimethylaminopyridine (102 mg) were suspended in o-dichlorobenzene (7ml), and the suspension was stirred at 140° C. for 4 hr and further at160° C. for 3 hr. The reaction solution was cooled to room temperature,and the solvent was then removed by distillation under the reducedpressure. The residue was purified by thin layer chromatography usingacetone-chloroform to give4-[2-(4-bromo-5-chloro-thiophen-2-yl)-quinolin-3-yloxy]-6,7-dimethoxy-quinoline(32 mg, yield 4%) (2 steps).

4-[2-(4-Bromo-5-chloro-thiophen-2-yl)-quinolin-3-yloxy]-6,7-dimethoxy-quinoline(20 mg) was dissolved in dioxane (3 ml) to prepare a solution.Tetrakistriphenylphosphine palladium (25 mg), methylboronic acid (0.1ml), water (0.3 ml), and cesium carbonate (182 mg) were added to thesolution, and the mixture was stirred at 100° C. for 4 days. Thereaction solution was filtered, and the solvent was removed bydistillation under the reduced pressure. The residue was purified bythin layer chromatography using methanol-chloroform to give the titlecompound (13 mg, yield 76%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.10 (s, 3H), 4.05 (s, 3H), 4.09 (s, 3H),6.59 (d, J=5.1 Hz, 1H), 7.50 (s, 1H), 7.52 (m, 1H), 7.62 (s, 1H),7.67-7.72 (m, 3H), 7.79 (s, 1H), 8.11 (d, J=8.5 Hz, 1H), 8.54 (d, J=5.4Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 485 (M+Na)⁺

Compound 2914-(4-Bromo-2-methyl-quinolin-3-yloxy)-6,7-dimethoxy-quinoline

3-Hydroxy-2-methyl-quinoline (76 mg) was dissolved in chlorobenzene (7ml) to prepare a solution. N-Bromosuccimide (180 mg) and2,2′-azobisisobutyronitrile (23 mg) were added to the solution, and themixture was stirred at 80° C. for one hr. Water was added to thereaction solution, and the mixture was extracted with ethyl acetate. Theethyl acetate layer was then washed with water and was dried overanhydrous sodium sulfate. The solvent was removed by distillation underthe reduced pressure, and the residue was purified by thin layerchromatography using acetone-chloroform to give4-bromo-3-hydroxy-2-methyl-quinoline (35 mg, yield 31%).

4-Bromo-3-hydroxy-2-methyl-quinoline (35 mg),4-chloro-6,7-dimethoxyquinoline (110 mg), and 4-dimethylaminopyridine(89 mg) were suspended in o-dichlorobenzene (5 ml), and the suspensionwas stirred at 140° C. for 5 hr. The reaction solution was cooled toroom temperature, and the solvent was removed by distillation under thereduced pressure. The residue was purified by thin layer chromatographyusing acetone-chloroform to give the title compound (20 mg, yield 32%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.64 (s, 3H), 4.08 (s, 3H), 4.12 (s, 3H),6.18 (d, J=5.1 Hz, 1H), 7.49 (s, 1H), 7.68 (m, 1H), 7.71 (s, 1H), 7.79(m, 1H), 8.12 (dd, J=3.2, 8.3 Hz, 1H), 8.18 (d, J=9.0 Hz, 1H), 8.46 (d,J=5.4 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 871 (2M+Na)⁺

Compound 2924-(6-Fluoro-2-phenyl-quinolin-3-yloxy)-6,7-dimethoxy-quinoline

5-Fluoro-1H-indole-2,3-dione (1.19 g) and 2-hydroxy-1-phenyl-ethanone(2.25 g) were dissolved in methanol (70 ml) to prepare a solution.Sodium hydroxide (4.82 g) and water (30 ml) were added to the solution,and the mixture was stirred at room temperature overnight. Dilutehydrochloric acid was added to the reaction solution, and theprecipitated crystal was washed with methanol and water to give6-fluoro-3-hydroxy-2-phenyl-quinoline-4-carboxylic acid (427 mg, yield21%).

6-Fluoro-3-hydroxy-2-phenyl-quinoline-4-carboxylic acid (118 mg),4-chloro-6,7-dimethoxyquinoline (330 mg), and 4-dimethylaminopyridine(310 mg) were suspended in o-dichlorobenzene (8 ml), and the mixture wasstirred at 160° C. for 11 hr. The reaction solution was cooled to roomtemperature, water was then added to the reaction solution, and themixture was extracted with ethyl acetate. The organic layer was washedwith water and was dried over anhydrous sodium sulfate. The solvent wasremoved by distillation under the reduced pressure, and the residue waspurified by thin layer chromatography using acetone-chloroform to givethe title compound (32 mg, yield 18%).

¹H-NMR (CDCl₃, 400 MHz): δ 4.01 (s, 3H), 4.05 (s, 3H), 6.48 (d, J=5.1Hz, 1H), 7.34-7.53 (m, 7H), 7.87 (s, 1H), 7.96 (m, 2H), 8.22 (dd, J=5.1,9.3 Hz, 1H), 8.47 (d, J=5.4 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 427 (M+1)⁺

Compound 293 4-(1H-Indol-5-yloxy)-6,7-dimethoxy-quinoline

5-Hydroroxyindole (180 mg), 4-chloro-6,7-dimethoxyquinoline (100 mg),and 4-dimethylaminopyridine (110 mg) were suspended in o-dichlorobenzene(6 ml), and the mixture was stirred at 130° C. for 8 hr. The reactionsolution was cooled to room temperature, water was then added to thereaction solution, and the mixture was extracted with ethyl acetate. Theethyl acetate layer was then washed with water and saturated brine andwas dried over anhydrous sodium sulfate. The solvent was removed bydistillation under the reduced pressure, and the residue was purified bythin layer chromatography using acetone-hexane to give the titlecompound (10 mg, yield 7%).

¹H-NMR (CDCl₃, 400 MHz): δ 3.97 (s, 3H), 3.99 (s, 3H), 6.35 (d, J=5.6Hz, 1H), 6.51 (s, 1H), 6.96 (dd, J=8.8 Hz, 2.4 Hz, 1H), 7.25 (m, 1H),7.38 (m, 3H), 7.59 (s, 1H), 8.36 (d, J=5.6 Hz, 1H), 8.43 (brs, 1H)

Mass spectrometric value (ESI−MS, m/z): 321 (M+1)⁺

Compound 294 4-(7-Iodo-benzothiazol-6-yloxy)-6,7-dimethoxy-quinoline

6-Hydroxy-benzothiazole (0.39 g) and iodine (1.32 g) were dissolved inmethanol/water (15 ml/5 ml) to prepare a solution which was then stirredat room temperature for 2 days. An aqueous sodium sulfite solution wasadded to the reaction solution, and the mixture was extracted with ethylacetate. The ethyl acetate layer was then washed with water and wasdried over anhydrous sodium sulfate. The solvent was removed bydistillation under the reduced pressure, and the residue was purified bycolumn chromatography using acetone-chloroform to give6-hydroxy-7-iodo-benzothiazole (211 mg, yield 29%).

6-Hydroxy-7-iodo-benzothiazole (210 mg), 4-chloro-6,7-dimethoxyquinoline(567 mg), and 4-dimethylaminopyridine (390 mg) were suspended ino-dichlorobenzene (15 ml), and the suspension was stirred at 140° C. for3 hr. The reaction solution was cooled to room temperature, and thesolvent was removed by distillation under the reduced pressure. Waterwas then added to the residue, and the mixture was extracted with ethylacetate. The ethyl acetate layer was then washed with water and wasdried over anhydrous sodium sulfate. The solvent was removed bydistillation under the reduced pressure, and the residue was purified bycolumn chromatography using acetone-chloroform to give the titlecompound (151 mg, yield 43%).

¹H-NMR (CDCl₃, 400 MHz): δ 4.07 (s, 3H), 4.09 (s, 3H), 6.34 (d, J=5.1Hz, 1H), 7.34 (d, J=8.8 Hz, 1H), 7.47 (s, 1H), 7.64 (s, 1H), 8.18 (d,J=8.8 Hz, 1H), 8.50 (d, J=5.1 Hz, 1H), 9.14 (s, 1H)

Mass spectrometric value (ESI−MS, m/z): 465 (M+1)⁺

Compound 295 6,7-Dimethoxy-4-(7-phenyl-benzothiazol-6-yloxy)-quinoline

4-(7-Iodo-benzothiazol-6-yloxy)-6,7-dimethoxy-quinoline (compound 294)(40 mg), phenylboronic acid (40 mg), and tetrakistriphenylphosphinepalladium (20 mg) were dissolved in N,N-dimethylformamide (5 ml) toprepare a solution. A 2 M aqueous potassium carbonate solution (0.3 ml)was added to the reaction system, and the mixture was stirred at 80° C.for 20 min. Water was added to the reaction solution, and the mixturewas extracted with ethyl acetate. The ethyl acetate layer was thenwashed with water and was dried over anhydrous sodium sulfate. Thesolvent was removed by distillation under the reduced pressure, and theresidue was purified by thin layer chromatography usingacetone-chloroform to give the title compound (35 mg, yield 98%).

¹H-NMR (CDCl₃, 400 MHz): δ 3.99 (s, 3H), 4.02 (s, 3H), 6.45 (d, J=5.1Hz, 1H), 7.28-7.33 (m, 3H), 7.40 (s, 1H), 7.40 (s, 1H), 7.45 (d, J=8.8Hz, 1H), 7.53 (m, 2H), 8.19 (d, J=8.8 Hz, 1H), 8.46 (d, J=5.4 Hz, 1H),9.03 (s, 1H)

Mass spectrometric value (ESI−MS, m/z): 415 (M+1)⁺

Compound 296 6,7-Dimethoxy-4-(7-methyl-quinolin-6-yloxy)-quinoline

4-Methoxy-3-methylaniline (45.2 g) was dissolved in isopropanol (100 ml)to prepare a solution. Diethyl ethoxymethylenemalonate (71.3 g) wasadded to the solution, and the mixture was heated under reflux for 5min. The reaction solution was cooled, and the solvent was then removedby distillation under the reduced pressure. The residue was washed withether-hexane to give diethyl2-[(4-methoxy-3-methyl-phenylamino)-methylene]-malonate (76.9 g, yield76%).

Diethyl 2-[(4-methoxy-3-methyl-phenylamino)-methylene]-malonate (73.9 g)was dissolved in diphenyl ether (200 ml) to prepare a solution which wasthen stirred at 220° C. for 2 hr. The reaction solution was cooled toroom temperature, hexane was then added to the reaction solution, andthe precipitated crystal was collected by filtration to give ethyl6-methoxy-7-methyl-4-oxo-1,4-dihydro-quinoline-3-carboxylate (25.5 g,yield 35%).

Ethyl 6-methoxy-7-methyl-4-oxo-1,4-dihydro-quinoline-3-carboxylate (25.5g) was suspended in a 2 M aqueous sodium hydroxide solution (250 ml),and the mixture was heated under reflux for 4 hr. The reaction solutionwas cooled to room temperature, the aqueous layer was then washed withchloroform and was neutralized with dilute hydrochloric acid. Theprecipitated crystal was collected by filtration and was washed withwater, isopropanol, and hexane in that order to give6-methoxy-7-methyl-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid (22.1g, yield 98%).

6-Methoxy-7-methyl-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid (22 g)was suspended in diphenyl ether (200 ml), and the suspension was heatedunder reflux overnight. The reaction solution was cooled to roomtemperature, hexane was then added to the reaction solution, and theprecipitated crystal was collected by filtration to give6-methoxy-7-methyl-1H-quinolin-4-one (16.6 g, yield 93%).

6-Methoxy-7-methyl-1H-quinolin-4-one (73.9 g) was added to phosphorusoxychloride (160 ml), and the mixture was heated under reflux for 2 hr.The reaction solution was cooled to room temperature, and the solventwas then removed by distillation under the reduced pressure. Chloroformand water were added to the reaction solution, and the aqueous layer wasneutralized with an aqueous potassium hydroxide solution. The organiclayer was washed with water and saturated brine and was dried overanhydrous sodium sulfate. The solvent was removed by distillation underthe reduced pressure, hexane was added to the residue, and theprecipitated crystal was collected by filtration to give4-chloro-6-methoxy-7-methyl-quinoline (12.7 g, yield 71%).

4-Chloro-6-methoxy-7-methyl-quinoline (10.8 g) was dissolved indiisopropylethylamine/IMS (7.4 g/100 ml), 5% palladium carbon (0.5 g)was added to the solution, and the mixture was stirred under a hydrogengas atmosphere at room temperature overnight. The reaction solution wasfiltered, and the solvent was then removed by distillation under thereduced pressure to give 6-methoxy-7-methyl-quinoline (3 g, yield 33%).

6-Methoxy-7-methyl-quinoline (3 g) was added to an aqueous bromic acidsolution (30 ml), and the mixture was heated under reflux for 7 hr. Thereaction solution was cooled to room temperature, the aqueous layer wasthen neutralized with an aqueous sodium hydroxide solution and anaqueous sodium hydrogencarbonate solution. The organic layer wasextracted with ether, the solvent was removed by distillation under thereduced pressure, and the residue was washed with cooled ether to give6-hydroxy-7-methylquinoline (1.3 g, yield 47%).

6-Hydroxy-7-methylquinoline (180 mg), 4-chloro-6,7-dimethoxyquinoline(126 mg), and 4-dimethylaminopyridine (69 mg) were suspended ino-dichlorobenzene (3 ml), and the suspension was stirred at 140° C. for3 hr. The reaction solution was cooled to room temperature, water wasthen added to the reaction solution, and the mixture was extracted withethyl acetate. The ethyl acetate layer was then washed with water andsaturated brine and was dried over anhydrous sodium sulfate. The solventwas removed by distillation under the reduced pressure, and the residuewas purified by thin layer chromatography using acetone-chloroform togive the title compound (36 mg, yield 60%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.36 (s, 3H), 3.99 (s, 6H), 6.31 (d, J=5.2Hz, 1H), 7.31 (dd, J=8.4 Hz, 4.0 Hz, 1H), 7.42 (s, 1H), 7.44 (s, 1H),7.54 (s, 1H), 8.00 (m, 2H), 8.41 (d, J=5.2 Hz, 1H), 8.83 (dd, J=8.4 Hz,4.0 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 347 (M+1)⁺

Compound 297 6,7-Dimethoxy-4-(7-methoxy-quinolin-6-yloxy)-quinoline

6-Benzyloxy-4-chloro-7-methoxy-quinoline (525 mg) was dissolved intriethylamine/N,N-dimethylformamide (5 ml/20 ml) to prepare a solution.20% palladium hydroxide (1.52 g) was added to the solution, and themixture was stirred at room temperature under a hydrogen gas atmospherefor 6 hr. The reaction solution was filtered, and the solvent was thenremoved by distillation under the reduced pressure. Water was added tothe residue, the mixture was extracted with chloroform, and thechloroform layer was then washed with water and was dried over anhydroussodium sulfate. The solvent was removed by distillation under thereduced pressure, and the residue was purified by column chromatographyusing acetone-chloroform to give 6-hydroxy-7-methoxyquinoline (258 mg,yield 84%).

6-Hydroxy-7-methoxyquinoline (65 mg), 4-chloro-6,7-dimethoxyquinoline(100 mg), and 4-dimethylaminopyridine (148 mg) were suspended ino-dichlorobenzene (5 ml), and the suspension was stirred at 155° C.overnight. The reaction solution was cooled to room temperature. Waterwas then added thereto, and the mixture was extracted with ethylacetate. The ethyl acetate layer was washed with water and was driedover anhydrous sodium sulfate. The solvent was removed by distillationunder the reduced pressure, and the residue was purified by columnchromatography using acetone-chloroform to give the title compound (134mg, yield 100%).

¹H-NMR (CDCl₃, 400 MHz): δ 3.93 (s, 3H), 4.06 (s, 3H), 4.07 (s, 3H),6.38 (d, J=5.1 Hz, 1H), 7.34 (dd, J=4.4, 8.3 Hz, 1H), 7.45 (s, 1H), 7.56(s, 1H), 7.63 (s, 1H), 7.63 (s, 1H), 8.05 (d, J=8.1 Hz, 1H), 8.48 (d,J=5.1 Hz, 1H), 8.88 (dd, J=1.4, 4.4 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 363 (M+1)⁺

Compound 298 4-(5-Chloro-quinolin-6-yloxy)-6,7-dimethoxy-quinoline

6-Hydroxyquinoline (0.5 g) and iodine (1.24 g) were dissolved inmethanol/water (15 ml/7.5 ml) to prepare a solution which was thenstirred at room temperature for 2 hr. The solvent was removed bydistillation under the reduced pressure, water was added to the residue,and the mixture was extracted with ethyl acetate. The ethyl acetatelayer was then washed with water and was dried over anhydrous sodiumsulfate. The solvent was removed by distillation under the reducedpressure, and the residue was washed with ethyl acetate to give6-hydroxy-5-iodo-quinoline (419 mg, yield 45%).

6-Hydroxy-5-iodo-quinoline (100 mg), 4-chloro-6,7-dimethoxyquinoline(215 mg), and 4-dimethylaminopyridine (367 mg) were suspended ino-dichlorobenzene (12 ml), and the suspension was stirred at 120° C. for5 hr. The reaction solution was cooled to room temperature, and thesolvent was removed by distillation under the reduced pressure. Waterwas then added to the residue, and the mixture was extracted with ethylacetate. The ethyl acetate layer was then washed with water and wasdried over anhydrous sodium sulfate. The solvent was removed bydistillation under the reduced pressure, and the residue was purified bythin layer chromatography using acetone-chloroform to give the titlecompound (20 mg, yield 12%).

¹H-NMR (CDCl₃, 400 MHz): δ 4.08 (s, 3H), 4.09 (s, 3H), 6.35 (d, J=5.4Hz, 1H), 7.49 (s, 1H), 7.55-7.68 (m, 3H), 8.16 (d, J=9.0 Hz, 1H), 8.49(d, J=5.1 Hz, 1H), 8.65 (m, 1H), 9.01 (dd, J=1.7, 4.1 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 367 (M+1)⁺

Compound 299 6,7-Dimethoxy-4-(7-phenyl-quinolin-6-yloxy)-quinoline

Trifluoroacetic acid (15 ml) and methanesulfonic acid (1.5 ml) wereadded to 7-benzyloxy-4-chloro-6-methoxy-quinoline (1.02 g), and themixture was stirred at room temperature for one hr. The solvent wasremoved by distillation under the reduced pressure, water was then addedto the reaction solution, and the mixture was extracted with ethylacetate. The organic layer was washed with an aqueous sodiumhydrogencarbonate solution and water and was dried over anhydrous sodiumsulfate. The solvent was removed by distillation under the reducedpressure, and the residue (0.8 g) was used in the next reaction withoutpurification.

A part (545 g) of the residue was suspended intriethylamine/dichloromethane (5 ml/20 ml), trifluoromethanesulfonicanhydride (2 ml) was added to the suspension under ice cooling, and themixture was stirred at room temperature for 2 hr. The solvent wasremoved by distillation under the reduced pressure. Water was then addedto the reaction solution, and the mixture was extracted with ethylacetate. The organic layer was washed with an aqueous sodiumhydrogencarbonate solution and water and was dried over anhydrous sodiumsulfate. The solvent was removed by distillation under the reducedpressure, and the residue was purified by column chromatography usingethyl acetate-hexane to give 4-chloro-6-methoxy-quinolin-7-yltrifluoro-methanesulfonate (228 mg, yield 29%) (2 steps).

4-Chloro-6-methoxy-quinolin-7-yl trifluoro-methanesulfonate (114 mg),phenylboronic acid (150 mg), and tetrakistriphenylphosphine palladium(25 mg) were dissolved in N,N-dimethylformamide (3 ml), a 2 M aqueouspotassium carbonate solution (0.3 ml) was added to the reaction system,and the mixture was stirred at 80° C. for one hr. Water was added to thereaction solution, and the mixture was extracted with ethyl acetate, andthe ethyl acetate layer was then washed with water and was dried overanhydrous sodium sulfate. The solvent was removed by distillation underthe reduced pressure, and the residue was used in the next reactionwithout purification.

The residue was dissolved in triethylamine/N,N-dimethylformamide (2ml/10 ml) to prepare a solution, palladium hydroxide (0.83 g) was addedto the solution, and the mixture was stirred at room temperature under ahydrogen gas atmosphere overnight. The reaction solution was filtered,and the solvent was then removed by distillation under the reducedpressure. Water was added to the residue, and the mixture was extractedwith ethyl acetate. The ethyl acetate layer was then washed with waterand was dried over anhydrous sodium sulfate. The solvent was removed bydistillation under the reduced pressure, and the residue was purified bythin layer chromatography using ethyl acetate-hexane to give6-methoxy-7-phenyl-1,2,3,4-tetrahydro-quinoline (63 mg, yield 79%).

6-Methoxy-7-phenyl-1,2,3,4-tetrahydro-quinoline (62 mg) was dissolved ino-dichlorobenzene (20 ml) to prepare a solution.2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (227 mg) was added to thesolution, and the mixture was stirred at 120° C. for 30 min. Water wasadded to the reaction solution, and the mixture was extracted with ethylacetate. The ethyl acetate layer was then washed with water and wasdried over anhydrous sodium sulfate. The solvent was removed bydistillation under the reduced pressure, and the residue was used in thenext reaction without purification.

The residue was dissolved in dichloromethane (3 ml) to prepare asolution, a boron tribromide/1 M dichloromethane solution (0.3 ml) wasadded to the solution under ice cooling, and the mixture was stirred for2 days. The solvent was removed by distillation under the reducedpressure, water was then added to the residue, and the mixture wasextracted with ethyl acetate. The ethyl acetate layer was washed withwater and was dried over anhydrous sodium sulfate. The solvent wasremoved by distillation under the reduced pressure, and the residue wasused in the next reaction without purification.

The residue, 4-chloro-6,7-dimethoxyquinoline (62 mg), and4-dimethylaminopyridine (49 mg) were suspended in o-dichlorobenzene (2ml), and the suspension was stirred at 150° C. for 4 hr. The reactionsolution was cooled to room temperature, and the solvent was removed bydistillation under the reduced pressure. The residue was purified bythin layer chromatography using acetone-chloroform to give the titlecompound (24 mg, yield 23%) (3 steps).

¹H-NMR (CDCl₃, 400 MHz): δ 4.01 (s, 3H), 4.03 (s, 3H), 6.47 (d, J=5.4Hz, 1H), 7.23-7.32 (m, 3H), 7.38 (s, 1H), 7.44-7.47 (m, 2H), 7.61-7.63(m, 3H), 8.12 (d, J=7.8 Hz, 1H), 8.30 (s, 1H), 8.43 (d, J=5.1 Hz, 1H),8.97 (dd, J=1.7, 4.2 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 409 (M+1)⁺

Compound 300 6,7-Dimethoxy-4-(7-methyl-isoquinolin-6-yloxy)-quinoline

4-Methoxy-3-methylbenzaldehyde (3.00 g) was dissolved in benzene (30 ml)to prepare a solution. 2,2-Dimethoxy-ethylamine (2.10 g) was added tothe solution, and the mixture was heated under reflux overnight. Thesolvent was removed by distillation under the reduced pressure, theresidue was then dissolved in tetrahydrofuran (30 ml), and the mixturewas cooled to −10° C. Ethyl chloroformate (2.17 g) and trimethylphosphite (2.97 g) were added thereto, and mixture was stirred at roomtemperature overnight. The solvent was removed by distillation under thereduced pressure, the residue was then dissolved in dichloromethane (30ml), titanium tetrachloride (22.7 g) was added to the solution, and themixture was heated under reflux for 36 hr. The reaction solution wascooled to room temperature, was then neutralized with a 1 N aqueoussodium hydroxide solution, and was extracted with 3 N hydrochloric acid.The aqueous layer was made basic by the addition of a 3 N aqueous sodiumhydroxide solution and was then extracted with dichloromethane. Thesolvent was removed by distillation under the reduced pressure to give6-methoxy-7-methylisoquinoline (764 mg, yield 22%).

6-Methoxy-7-methylisoquinoline (239 mg) and sodium thiomethoxide (1.58g) were suspended in N,N-dimethylformamide (12 ml), and the suspensionwas stirred at 160° C. for 2 hr. The reaction solution was cooled toroom temperature, the reaction solution was then filtered, and thesolvent was removed from the filtrate by distillation under the reducedpressure. The residue was purified by thin layer chromatography usingchloroform-methanol to give 6-hydroxy-7-methylisoquinoline (21 mg, yield1%).

6-Hydroxy-7-methylisoquinoline (21 mg), 4-chloro-6,7-dimethoxyquinoline(81 mg), and 4-dimethylaminopyridine (44 mg) were suspended ino-dichlorobenzene (2.5 ml), and the suspension was stirred at 140° C.for 6 hr. The reaction solution was cooled to room temperature, waterwas then added to reaction solution, and the mixture was extracted withethyl acetate. The ethyl acetate layer was then washed with water andsaturated brine and was dried over anhydrous sodium sulfate. The solventwas removed by distillation under the reduced pressure, and the residuewas purified by thin layer chromatography using acetone-chloroform togive the title compound (24 mg, yield 58%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.37 (s, 3H), 3.96 (s, 3H), 3.99 (s, 3H),6.35 (d, J=5.2 Hz, 1H), 7.36 (s, 1H), 7.39 (s, 1H), 7.47 (m, 2H), 7.86(s, 1H), 8.41 (d, J=5.6 Hz, 1H), 8.44 (d, J=5.2 Hz, 1H), 9.15 (s, 1H)

Mass spectrometric value (ESI−MS, m/z): 347 (M+1)⁺

Compound 301 4-(7-Bromo-isoquinolin-6-yloxy)-6,7-dimethoxy-quinoline

3-Bromo-4-methoxybenzaldehyde (10.0 g) was dissolved in benzene (100 ml)to prepare a solution. 2,2-Dimethoxy-ethylamine (4.89 g) was added tothe solution, and the mixture was heated under reflux overnight. Thesolvent was removed by distillation under the reduced pressure, and theresidue was then dissolved in tetrahydrofuran (100 ml) to prepare asolution which was then cooled to −10° C. Ethyl chloroformate (5.05 g)and trimethyl phosphite (6.92 g) were added thereto, and the mixture wasstirred at room temperature overnight. The solvent was removed bydistillation under the reduced pressure, the residue was then dissolvedin dichloromethane (100 ml) to prepare a solution. Titaniumtetrachloride (53.0 g) was added to the solution, and the mixture washeated under reflux for 36 hr. The reaction solution was cooled to roomtemperature, was then neutralized with a 1 N aqueous sodium hydroxidesolution, and was extracted with 3 N hydrochloric acid. The aqueouslayer was made basic with a 3 N aqueous sodium hydroxide solution, wasthen extracted with dichloromethane, and the solvent was removed bydistillation under the reduced pressure to give7-bromo-6-methoxyisoquinoline (2.90 g, yield 26%).

7-Bromo-6-methoxyisoquinoline (50 mg) and sodium thiomethoxide (147 mg)were suspended in N,N-dimethylformamide (2 ml), and the suspension wasstirred at 150° C. for 2 hr. The reaction solution was cooled to roomtemperature, the reaction solution was then filtered, and the solventwas removed from the filtrate by distillation under the reducedpressure. The residue was purified by thin layer chromatography usingchloroform-methanol to give 7-bromo-6-hydroxyisoquinoline (11 mg, yield22%).

7-Bromo-6-hydroxyisoquinoline (11 mg), 4-chloro-6,7-dimethoxyquinoline(31 mg), and 4-dimethylaminopyridine (17 mg) were suspended ino-dichlorobenzene (2 ml), and the mixture was stirred at 140° C. for 7hr. The reaction solution was cooled to room temperature, water was thenadded to the reaction solution, and the mixture was extracted with ethylacetate. The ethyl acetate layer was then washed with water andsaturated brine and was dried over anhydrous magnesium sulfate. Thesolvent was removed by distillation under the reduced pressure, and theresidue was purified by thin layer chromatography usingchloroform-methanol to give the title compound (9 mg, yield 48%).

¹H-NMR (CDCl₃, 400 MHz): δ 3.97 (s, 3H), 3.99 (s, 3H), 6.44 (d, J=5.2Hz, 1H), 7.40 (s, 1H), 7.49 (m, 3H), 8.32 (s, 1H), 8.50 (m, 2H), 9.17(s, 1H)

Mass spectrometric value (ESI−MS, m/z): 412 (M+1)⁺

Compound 3024-(5-Chloro-7-methyl-quinolin-6-yloxy)-6,7-dimethoxy-quinoline

6-Hydroxy-7-methylquinoline (76 mg) was dissolved in chlorobenzene (7ml) to prepare a solution. N-Bromosuccimide (180 mg) and2,2′-azobisisobutyronitrile (23 mg) were added to the solution, and themixture was stirred at 80° C. for one hr. Water was added to thereaction solution, and the mixture was extracted with ethyl acetate. Theethyl acetate layer was then washed with water and was dried overanhydrous sodium sulfate, the solvent was removed by distillation underthe reduced pressure, and the residue was purified by thin layerchromatography using acetone-chloroform to give5-bromo-6-hydroxy-7-methyl-quinoline (111 mg, yield 97%).

5-Bromo-6-hydroxy-7-methyl-quinoline (110 mg),4-chloro-6,7-dimethoxyquinoline (330 mg), and 4-dimethylaminopyridine(240 mg) were suspended in o-dichlorobenzene (10 ml), and the mixturewas stirred at 140° C. for 6 hr. The reaction solution was cooled toroom temperature, and the solvent was removed therefrom by distillationunder the reduced pressure. The residue was purified by thin layerchromatography using acetone-chloroform to give the title compound (19mg, yield 10%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.42 (s, 3H), 4.08 (s, 3H), 4.12 (s, 3H),6.18 (d, J=5.4 Hz, 1H), 7.49 (s, 1H), 7.53 (dd, J=4.3, 8.6 Hz, 1H), 7.72(s, 1H), 8.04 (s, 1H), 8.44 (d, J=5.1 Hz, 1H), 8.56 (d, J=8.6 Hz, 1H),8.98 (dd, J=1.3, 4.4 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 783 (2M+Na)⁺

Compound 3036,7-Dimethoxy-4-(7-pyridin-2-yl-isoquinolin-6-yloxy)-quinoline

7-Bromo-6-methoxyisoquinoline (200 mg), tetrakistriphenylphosphinepalladium(0) (97 mg), and copper(II) oxide (134 mg) were suspended inN,N-dimethylformamide (5 ml), tri-n-butyl-(2-pyridyl)-tin (618 mg) wasadded to the suspension, and the mixture was stirred at 100° C.overnight. The reaction solution was cooled to room temperature, thereaction solution was then filtered, and the solvent was removed fromthe filtrate by distillation under the reduced pressure. Water was thenadded to the residue, and the mixture was extracted withdichloromethane. The dichloromethane layer was washed with water andsaturated brine and was dried over anhydrous magnesium sulfate. Thesolvent was removed by distillation under the reduced pressure, and theresidue was purified by thin layer chromatography usingchloroform-methanol to give 6-methoxy-7-pyridin-2-yl-isoquinoline (122mg, yield 62%).

6-Methoxy-7-pyridin-2-yl-isoquinoline (118 mg) and sodium thiomethoxide(350 mg) were suspended in N,N-dimethylformamide (3 ml), and the mixturewas stirred at 150° C. for 4 hr. The reaction solution was cooled toroom temperature, the reaction solution was then filtered, and thesolvent was removed from the filtrate by distillation under the reducedpressure. The residue was purified by thin layer chromatography usingchloroform-methanol to give 7-pyridin-2-yl-isoquinolin-6-ol (30 mg,yield 27%).

7-Pyridin-2-yl-isoquinolin-6-ol (20 mg), 4-chloro-6,7-dimethoxyquinoline(50 mg), and 4-dimethylaminopyridine (33 mg) were suspended ino-dichlorobenzene (3 ml), and the mixture was stirred at 140° C. for 24hr. The reaction solution was cooled to room temperature, water was thenadded to the reaction solution, and the mixture was extracted with ethylacetate. The ethyl acetate layer was then washed with water andsaturated brine and was dried over anhydrous magnesium sulfate. Thesolvent was removed by distillation under the reduced pressure, and theresidue was purified by thin layer chromatography usingchloroform-methanol to give the title compound (8 mg, yield 22%).

¹H-NMR (CDCl₃, 400 MHz): δ 3.93 (s, 3H), 3.97 (s, 3H), 6.27 (d, J=5.2Hz, 1H), 7.12 (m, 1H), 7.34 (s, 1H), 7.41 (s, 1H), 7.51 (m, 3H), 7.71(d, J=7.6 Hz, 1H), 8.40 (d, J=5.2 Hz, 1H), 8.49 (d, J=6.0 Hz, 1H), 8.52(s, 1H), 8.60 (d, J=4.4 Hz, 1H), 9.31 (s, 1H)

Mass spectrometric value (ESI−MS, m/z): 432 (M+Na)⁺

Compound 3046,7-Dimethoxy-4-(7-pyridin-3-yl-isoquinolin-6-yloxy)-quinoline

7-Bromo-6-methoxyisoquinoline (100 mg), tetrakistriphenylphosphinepalladium(0) (49 mg), and 3-pyridineboronic acid (155 mg) were suspendedin a mixed solvent composed of N,N-dimethylformamide (1.5 ml) and a 2 Naqueous potassium carbonate solution (1.5 ml), and the mixture wasstirred at 80° C. for 4.5 hr. The reaction was cooled to roomtemperature, the reaction solution was then filtered, and the solventwas removed from the filtrate by distillation under the reducedpressure. Water was then added to the residue, and the mixture wasextracted with dichloromethane. The dichloromethane layer was washedwith water and saturated brine and was dried over anhydrous magnesiumsulfate. The solvent was removed by distillation under the reducedpressure, and the residue was purified by thin layer chromatographyusing chloroform-methanol to give 6-methoxy-7-pyridin-3-yl-isoquinoline(42 mg, yield 85%).

6-Methoxy-7-pyridin-3-yl-isoquinoline (42 mg) and sodium thiomethoxide(126 mg) were suspended in N,N-dimethylformamide (1.5 ml), and themixture was stirred at 160° C. for 2 hr. The reaction solution wascooled to room temperature, the reaction solution was then filtered, andthe solvent was removed from the filtrate by distillation under thereduced pressure. The residue was purified by thin layer chromatographyusing chloroform-methanol to give 7-pyridin-3-yl-isoquinolin-6-ol (7 mg,yield 17%).

7-Pyridin-3-yl-isoquinolin-6-ol (7 mg), 4-chloro-6,7-dimethoxyquinoline(21 mg), and 4-dimethylaminopyridine (12 mg) were suspended ino-dichlorobenzene (1.5 ml), and the suspension was stirred at 140° C.for 4 hr. The reaction solution was cooled to room temperature, waterwas then added to the reaction solution, and the mixture was extractedwith ethyl acetate. The ethyl acetate layer was then washed with waterand saturated brine and was dried over anhydrous magnesium sulfate. Thesolvent was removed by distillation under the reduced pressure, and theresidue was purified by thin layer chromatography usingchloroform-methanol to give the title compound (7 mg, yield 55%).

¹H-NMR (CDCl₃, 400 MHz): δ 3.91 (s, 3H), 3.96 (s, 3H), 6.48 (d, J=5.2Hz, 1H), 7.19 (m, 1H), 7.28 (s, 1H), 7.34 (s, 1H), 7.50 (s, 1H), 7.54(d, J=5.6 Hz, 1H), 7.85 (d, J=7.6 Hz, 1H), 8.08 (s, 1H), 8.46 (m, 3H),8.83 (s, 1H), 9.28 (s, 1H)

Mass spectrometric value (ESI−MS, m/z): 432 (M+Na)⁺

Compound 305 6-(6,7-Dimethoxy-quinolin-4-yloxy)-7-methyl-quinazoline

3-Hydroxy-4-methylbenzoic acid (3 g) was dissolved inN,N-dimethylformamide (60 ml) to prepare a solution. Potassium carbonate(6.81 g) and methyl iodide (6.14 ml) were added to the solution, and themixture was stirred at room temperature overnight. Water was added tothe reaction solution, and the mixture was extracted with ethyl acetate.The ethyl acetate layer was then washed with saturated brine and wasdried over anhydrous sodium sulfate. The solvent was removed bydistillation under the reduced pressure, and the residue was purified bycolumn chromatography using acetone-hexane to give methyl3-methoxy-4-methylbenzoate (3.48 g, yield 98%).

Methyl 3-methoxy-4-methylbenzoate (1 g) was dissolved in acetic acid (1ml) to prepare a solution which was then cooled to 0° C. Fuming nitricacid (1 ml) was added to the solution in small portions. The mixture wasstirred at room temperature overnight. The reaction solution was addedin small portions to water of 0° C., and the mixture was neutralizedwith a 10% aqueous sodium hydroxide solution, followed by extractionwith chloroform. The chloroform layer was then washed with saturatedbrine and was dried over anhydrous sodium sulfate. The solvent wasremoved by distillation under the reduced pressure, and the residue wasused in the next reaction without purification.

The residue (1.02 g) was dissolved in N,N-dimethylformamide (15 ml) toprepare a solution. Triethylamine (3 ml) and 20% palladium hydroxide(150 mg) were added to the solution, and the mixture was stirred underhydrogen pressure at room temperature overnight. The reaction solutionwas filtered through Celite and was then washed with chloroform andmethanol. The solvent was removed by distillation under the reducedpressure, and the residue was purified by column chromatography usingacetone-hexane to give methyl 2-amino-5-methoxy-4-methylbenzoate (522mg, yield 48%).

Methyl 2-amino-5-methoxy-4-methylbenzoate (510 mg) was suspended informamide (5 ml), and the suspension was stirred at 140° C. overnight.The precipitated crystal was washed with ether to give6-methoxy-7-methyl-1H-quinazolin-4-one (275 mg, yield 55%).

6-Methoxy-7-methyl-1H-quinazolin-4-one (275 mg) was suspended inN,N-diisopropylethylamine (3.78 ml), phosphorus oxychloride (0.3 ml) wasadded to the suspension, and the mixture was stirred at 100° C. for 6hr. The reaction solution was added in small portions to water of 0° C.,an aqueous sodium hydrogencarbonate solution was further added thereto,and the mixture was extracted with chloroform. The chloroform layer wasthen washed with saturated brine and was dried over anhydrous sodiumsulfate. The solvent was removed by distillation under the reducedpressure, and the residue was purified by thin layer chromatographyusing chloroform-methanol to give4-chloro-6-methoxy-7-methyl-quinazoline (199 mg, yield 66%).

4-Chloro-6-methoxy-7-methyl-quinazoline (99 mg) was dissolved inN,N-dimethylformamide (6 ml) to prepare a solution. Triethylamine (0.6ml) and 20% palladium hydroxide (4 mg) were added to the solution, andthe mixture was stirred under hydrogen pressure at room temperatureovernight. The reaction solution was filtered through Celite and wasthen washed with chloroform and methanol, and the solvent was removed bydistillation under the reduced pressure. Water was added to the residue,and the mixture was extracted with ethyl acetate. The ethyl acetatelayer was then washed with saturated brine and was dried over anhydroussodium sulfate. The solvent was removed by distillation under thereduced pressure, and the residue was purified by thin layerchromatography using chloroform-methanol to give6-methoxy-7-methyl-quinazoline (76 mg, yield 93%).

6-Methoxy-7-methyl-quinazoline (94 mg) was dissolved inN,N-dimethylformamide (5 ml) to prepare a solution, sodium thiomethoxide(376 mg) was added to the solution, and the mixture was stirred at 140°C. for one hr. The solvent was removed by distillation under the reducedpressure, and the residue was purified by thin layer chromatographyusing chloroform-methanol to give 6-hydroxy-7-methyl-quinazoline (64 mg,yield 73%).

6-Hydroxy-7-methyl-quinazoline (38 mg), 4-chloro-6,7-dimethoxyquinoline(159 mg), and 4-dimethylaminopyridine (87 mg) were suspended ino-dichlorobenzene (2 ml), and the suspension was stirred at 150° C.overnight. The reaction solution was cooled to room temperature, waterwas then added to the solution, and the mixture was extracted withchloroform. The chloroform layer was washed with saturated brine and wasdried over anhydrous sodium sulfate. The solvent was removed bydistillation under the reduced pressure, and the residue was purified bythin layer chromatography using chloroform-methanol to give the titlecompound (71 mg, yield 86%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.51 (s, 3H), 4.07 (s, 3H), 4.10 (s, 3H),6.45 (d, J=5.4 Hz, 1H), 7.57-7.59 (m, 3H), 8.06 (s, 1H), 8.53 (d, J=5.4Hz, 1H), 9.31 (s, 1H), 9.34 (s, 1H)

Mass spectrometric value (ESI−MS, m/z): 348 (M+1)⁺

Compound 306 6-(6,7-Dimethoxy-quinolin-4-yloxy)-4-methyl-chromen-2-one

6-Hydroxy-4-methyl-chromen-2-one (238 mg),4-chloro-6,7-dimethoxyquinoline (100 mg), and 4-dimethylaminopyridine(165 mg) were suspended in o-dichlorobenzene (5 ml), and the suspensionwas stirred at 140° C. for 3.5 hr. The reaction solution was cooled toroom temperature, water was then added to the reaction solution, and themixture was extracted with ethyl acetate. The ethyl acetate layer wasthen washed with water and saturated brine and was dried over anhydroussodium sulfate. The solvent was removed by distillation under thereduced pressure, and the residue was purified by thin layerchromatography using acetone-chloroform to give the title compound (24mg, yield 5%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.34 (s, 3H), 3.98 (s, 6H), 6.30 (s, 1H),6.35 (d, J=5.2 Hz, 1H), 7.28-7.42 (m, 4H), 7.48 (s, 1H), 8.43 (d, J=5.2Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 749 (2M+Na)⁺

Compound 307 6,7-Dimethoxy-4-(thieno[3,2-b]pyridin-7-yloxy)-quinoline

Thieno[3,2-b]pyridin-7-ol (203 mg), 4-chloro-6,7-dimethoxyquinoline (100mg), and 4-dimethylaminopyridine (110 mg) were suspended ino-dichlorobenzene (6 ml), and the suspension was stirred at 130° C. for8 hr. The reaction solution was cooled to room temperature, water wasthen added to the reaction solution, and the mixture was extracted withethyl acetate. The ethyl acetate layer was then washed with water andsaturated brine and was dried over anhydrous sodium sulfate. The solventwas removed by distillation under the reduced pressure, and the residuewas purified by thin layer chromatography using acetone-hexane to givethe title compound (4 mg, yield 1%).

¹H-NMR (CDCl₃, 400 MHz): δ 3.89 (s, 3H), 4.00 (s, 3H), 6.77 (m, 2H),7.31 (s, 1H), 7.44 (s, 1H), 7.57 (d, J=5.6 Hz, 1H), 7.73 (d, J=5.6 Hz,1H), 8.57 (m, 2H)

Mass spectrometric value (ESI−MS, m/z): 339 (M+1)⁺

Compound 3086,7-Dimethoxy-4-(6-fluoro-2-methyl-quinolin-4-yloxy)-quinoline

6-Fluoro-2-methyl-quinolin-4-ol (237 mg),4-chloro-6,7-dimethoxyquinoline (100 mg), and 4-dimethylaminopyridine(164 mg) were suspended in o-dichlorobenzene (6 ml), and the suspensionwas stirred at 130° C. overnight. The reaction solution was cooled toroom temperature, water was then added to the reaction solution, and themixture was extracted with ethyl acetate. The ethyl acetate layer wasthen washed with water and saturated brine and was dried over anhydroussodium sulfate. The solvent was removed by distillation under thereduced pressure, and the residue was purified by thin layerchromatography using acetone-chloroform to give the title compound (11mg, yield 7%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.57 (s, 3H), 3.88 (s, 3H), 4.00 (s, 3H),6.69 (m, 2H), 7.29 (s, 1H), 7.45 (m, 2H), 7.72 (dd, J=8.8 Hz, 2.8 Hz,1H), 8.00 (m, 1H), 8.57 (s, 1H)

Mass spectrometric value (ESI−MS, m/z): 365 (M+1)⁺

Compound 309 6,7-Dimethoxy-4-(2-methyl-quinolin-4-yloxy)-quinoline

2-Methyl-quinolin-4-ol (213 mg), 4-chloro-6,7-dimethoxyquinoline (100mg), and 4-dimethylaminopyridine (110 mg) were suspended ino-dichlorobenzene (6 ml), and the suspension was stirred at 130° C.overnight. The reaction solution was cooled to room temperature, waterwas then added to the reaction solution, and the mixture was extractedwith ethyl acetate. The ethyl acetate layer was then washed with waterand saturated brine and was dried over anhydrous sodium sulfate. Thesolvent was removed by distillation under the reduced pressure, and theresidue was purified by thin layer chromatography using acetone-hexaneto give the title compound (7 mg, yield 2%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.60 (s, 3H), 3.88 (s, 3H), 4.00 (s, 3H),6.68 (d, J=5.2 Hz, 1H), 6.70 (s, 1H), 7.34 (s, 1H), 7.45 (m, 2H), 7.70(m, 1H), 8.02 (d, J=8.4 Hz, 1H), 8.11 (d, J=8.4 Hz, 1H), 8.55 (d, J=5.2Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 347 (M+1)⁺

Compound 3103-(6,7-Dimethoxy-quinolin-4-yloxy)-2-methyl-[1,8]naphthyridine

2-Aminopyridine (14.1 g) and triethylamine (19.0 g) were dissolved indichloromethane (200 ml) to prepare a solution which was then cooled at0° C. A solution of pivaloylic acid chloride (19.9 g) in dichloromethane(30 ml) was gradually added dropwise to the solution, and the mixturewas stirred at 0° C. for 15 min. Thereafter, the mixture was stirred atroom temperature for 4 hr, and the reaction solution was poured intowater (150 ml). The dichloromethane layer was washed with a diluteaqueous sodium hydrogencarbonate solution and was dried over anhydroussodium sulfate. The solvent was removed by distillation under thereduced pressure. The residue was purified by column chromatographyusing chloroform to give 2,2-dimethyl-N-pyridin-2-yl-propionamide (25.2g, yield 95%).

2,2-Dimethyl-N-pyridin-2-yl-propionamide (20.3 g) was dissolved intetrahydrofuran (230 ml) to prepare a solution which was then cooled to−78° C. A 2.44 M n-butyllithium/n-hexane solution (100 ml) was graduallyadded dropwise thereto, and the mixture was stirred at −78° C. for 15min. The reaction solution was stirred at 0° C. for 2 hr and was thenagain cooled to −78° C. A solution of N,N-dimethylformamide (25.0 g) intetrahydrofuran (25 ml) was gradually added dropwise thereto. Thetemperature of the mixture was raised to room temperature. The reactionsolution was then poured into a mixture of ice (50 g) and 6 Nhydrochloric acid (150 ml), and the mixture was stirred at roomtemperature for 20 min. The aqueous layer was neutralized with potassiumcarbonate powder and was extracted with diethyl ether. The diethyl etherlayer was then washed with water and saturated brine and was dried overmagnesium sulfate. The solvent was removed by distillation under thereduced pressure, and the residue was purified by column chromatographyusing acetone-chloroform to giveN-(3-formyl-pyridin-2-yl)-2,2-dimethyl-propionamide (11.8 g, yield 50%).

N-(3-Formyl-pyridin-2-yl)-2,2-dimethyl-propionamide (9.68 g) wasdissolved in 3 N hydrochloric acid (140 ml) to prepare a solution whichwas then stirred under reflux overnight. The reaction solution wascooled to room temperature, the reaction solution was washed withdiethyl ether, and was neutralized with potassium carbonate powder.Diethyl ether was added thereto for extraction. The diethyl ether layerwas dried over potassium carbonate. The solvent was removed bydistillation under the reduced pressure, and the residue was purified bycolumn chromatography using acetone-chloroform to give2-amino-pyridine-3-carbaldehyde (5.03 g, yield 88%).

2-Amino-pyridine-3-carbaldehyde (2.0 g) and chloroacetone (1.5 g) weresuspended in a 5 N aqueous sodium hydroxide solution (10 ml) and wasallowed to stand in a hermetically sealed state for 3 days. The reactionsolution was neutralized with 10% hydrochloric acid, and theprecipitated crystal was then collected by filtration. Isopropanol wasadded to the crystal, and the mixture was heated under reflux. Thereaction solution was cooled to room temperature, and the solvent wasthen removed by distillation. Hexane was added to the residue, and theprecipitated crystal was collected by filtration and was washed withhexane to give 2-methyl-[1,8]naphthyridin-3-ol (1.05 g, yield 40%).

2-Methyl-[1,8]naphthyridin-3-ol (20 mg), 4-chloro-6,7-dimethoxyquinoline(84 mg), and 4-dimethylaminopyridine (46 mg) were suspended ino-dichlorobenzene (2 ml), and the suspension was stirred at 140° C. for3 hr. The reaction solution was cooled to room temperature, water wasthen added to the reaction solution, and the mixture was extracted withethyl acetate. The ethyl acetate layer was then washed with water andsaturated brine and was dried over anhydrous sodium sulfate. The solventwas removed by distillation under the reduced pressure, and the residuewas purified by thin layer chromatography using chloroform-methanol togive the title compound (41 mg, yield 100%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.68 (s, 3H), 3.97 (s, 3H), 3.99 (s, 3H),6.36 (d, J=5.2 Hz, 1H), 7.40 (m, 2H), 7.46 (s, 1H), 7.70 (s, 1H), 8.03(dd, J=8.4 Hz, 2.0 Hz, 1H), 8.46 (d, J=5.2 Hz, 1H), 9.01 (d, J=2.0 Hz,1H)

Mass spectrometric value (ESI−MS, m/z): 370 (M+Na)⁺

Compound 3113-(6,7-Dimethoxy-quinolin-4-yloxy)-2-methyl-[1,6]naphthyridine

4-Aminopyridine (4.70 g) and triethylamine (6.31 g) were dissolved indichloromethane (75 ml) to prepare a solution which was cooled to 0° C.A solution of pivaloylic acid chloride (6.63 g) in dichloromethane (10ml) was gradually added dropwise thereto, and the mixture was stirred at0° C. for 15 min. Thereafter, the mixture was stirred at roomtemperature overnight, and the reaction solution was poured into water(50 ml). The dichloromethane layer was washed with a dilute aqueoussodium hydrogencarbonate solution and was dried over anhydrous sodiumsulfate. The solvent was removed by distillation under the reducedpressure, and the residue was purified by column chromatography usingchloroform to give 2,2-dimethyl-N-pyridin-4-yl-propionamide (7.70 g,yield 87%).

2,2-Dimethyl-N-pyridin-4-yl-propionamide (5.60 g) was dissolved intetrahydrofuran (70 ml) to prepare a solution which was then cooled to−78° C. A 1.57 M n-butyllithium/n-hexane solution (62 ml) was graduallyadded dropwise thereto, and the mixture was stirred at −78° C. for 15min. The reaction solution was stirred at 0° C. for 4 hr and was thenagain cooled to −78° C. A solution of N,N-dimethylformamide (6.69 g) intetrahydrofuran (7 ml) was gradually added dropwise thereto. Thetemperature of the reaction solution was raised to room temperature, thereaction solution was then poured into a mixture composed of ice (10 g)and 6 N hydrochloric acid (30 ml), and the mixture was stirred at roomtemperature for 15 min. The aqueous layer was neutralized with potassiumcarbonate powder and was extracted with diethyl ether. The diethyl etherlayer was then washed with water and saturated brine and was dried overmagnesium sulfate. The solvent was removed by distillation under thereduced pressure, and the residue was purified by column chromatographyusing acetone-chloroform to giveN-(3-formyl-pyridin-4-yl)-2,2-dimethyl-propionamide (3.35 g, yield 52%).

N-(3-Formyl-pyridin-4-yl)-2,2-dimethyl-propionamide (3.35 g) wasdissolved in 3 N hydrochloric acid (50 ml) to prepare a solution whichwas stirred under reflux for 5.5 hr. The reaction solution was cooled toroom temperature, the reaction solution was then washed with diethylether and was neutralized with potassium carbonate powder. Diethyl etherwas added thereto, and the mixture was extracted. The diethyl etherlayer was dried over potassium carbonate. The solvent was removed bydistillation under the reduced pressure, and the residue was purified bycolumn chromatography using acetone-chloroform to give4-amino-pyridine-3-carbaldehyde (1.12 g, yield 58%).

4-Amino-pyridine-3-carbaldehyde (1.0 g) and chloroacetone (0.7 g) weresuspended in a 5 N aqueous sodium hydroxide solution (5 ml), and thesuspension was allowed to stand in a sealed tube for 3 days. Thereaction solution was neutralized with 10% hydrochloric acid, and theprecipitated crystal was then collected by filtration. Isopropanol wasadded to the collected crystal, and the mixture was heated under reflux.The reaction solution was cooled to room temperature, and the solventwas then removed by distillation. Hexane was added to the residue, andthe precipitated crystal was collected by filtration and was washed withhexane to give 2-methyl-[1,6]naphthyridin-3-ol (0.60 g, yield 46%).

2-Methyl-[1,6]naphthyridin-3-ol (20 mg), 4-chloro-6,7-dimethoxyquinoline(84 mg), and 4-dimethylaminopyridine (46 mg) were suspended ino-dichlorobenzene (2 ml), and the suspension was stirred at 140° C. for3 hr. The reaction solution was cooled to room temperature, water wasthen added to the reaction solution, and the mixture was extracted withethyl acetate. The ethyl acetate layer was then washed with water andsaturated brine and was dried over anhydrous sodium sulfate. The solventwas removed by distillation under the reduced pressure, and the residuewas purified by thin layer chromatography using chloroform-methanol togive the title compound (23 mg, yield 55%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.67 (s, 3H), 3.98 (s, 3H), 4.00 (s, 3H),6.37 (d, J=5.2 Hz, 1H), 7.41 (s, 1H), 7.45 (s, 1H), 7.79 (s, 1H), 7.83(d, J=6.0 Hz, 1H), 8.48 (d, J=5.2 Hz, 1H), 8.68 (d, J=6.0 Hz, 1H), 9.10(s, 1H)

Mass spectrometric value (ESI−MS, m/z): 348 (M+1)⁺

Compound 3121-[2-(7-Hydroxy-6-methoxy-quinolin-4-yloxy)-5-methoxy-phenyl]-ethanone

2-Hydroxy-5-methoxyacetophenone (3.00 g),7-benzyloxy-4-chloro-6-methoxyquinoline (6.65 g), and4-dimethylaminopyridine (4.90 g) were suspended in o-dichlorobenzene (30ml), and the suspension was stirred at 180° C. for 2 hr. The reactionsolution was cooled to room temperature, and the solvent was thenremoved by distillation under the reduced pressure. Water was added tothe residue, and the mixture was extracted with chloroform. Thechloroform layer was then washed with water and saturated brine and wasdried over anhydrous magnesium sulfate. The solvent was removed bydistillation under the reduced pressure, and the residue was purified bycolumn chromatography using acetone-chloroform to give1-[2-(7-benzyloxy-6-methoxy-quinolin-4-yloxy)-5-methoxy-phenyl]-ethanone(2.53 g, yield 59%).

1-[2-(7-Benzyloxy-6-methoxy-quinolin-4-yloxy)-5-methoxy-phenyl]-ethanone(2.52 g) was suspended in a mixed solution composed of methanesulfonicacid (3 ml) and trifluoroacetic acid (50 ml), and the suspension wasstirred at 70° C. for 30 min. The solvent was removed by distillationunder the reduced pressure, water was added to the residue, and themixture was neutralized with sodium hydrogencarbonate powder and wasthen extracted with chloroform. The chloroform layer was then washedwith water and saturated brine and was dried over anhydrous magnesiumsulfate, the solvent was removed by distillation under the reducedpressure, and the residue was purified by column chromatography usingchloroform-methanol to give the title compound (1.23 g, yield 62%).

¹H-NMR (DMSO-d₆, 400 MHz): δ 2.50 (s, 3H), 3.91 (s, 3H), 4.00 (s, 3H),6.35 (d, J=5.2 Hz, 1H), 7.34 (m, 3H), 7.42 (s, 1H), 7.61 (s, 1H), 8.45(d, J=5.2 Hz, 1H), 10.23 (brs, 1H)

Mass spectrometric value (ESI−MS, m/z): 338 (M−1)⁻

Compound 3131-[2-(7-Benzyloxy-6-methoxy-quinolin-4-yloxy)-4,5-dimethyl-phenyl]-ethanone

2-Hydroxy-4,5-dimethylacetophenone (3.63 g),7-benzyloxy-4-chloro-6-methoxyquinoline (1.50 g), and4-dimethylaminopyridine (2.71 g) were suspended in o-dichlorobenzene (15ml), and the suspension was stirred at 130° C. overnight. The reactionsolution was cooled to room temperature, and the solvent was thenremoved by distillation under the reduced pressure. Water was added tothe residue, and the mixture was extracted with chloroform, and thechloroform layer was then washed with water and saturated brine and wasdried over anhydrous magnesium sulfate. The solvent was removed bydistillation under the reduced pressure, and the residue was purified bycolumn chromatography using acetone-hexane to give the title compound(1.10 g, yield 37%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.23 (s, 3H), 2.26 (s, 3H), 2.43 (s, 3H),3.98 (s, 3H), 5.24 (s, 2H), 6.35 (d, J=5.2 Hz, 1H), 6.87 (s, 1H),7.22-7.36 (m, 3H), 7.47 (m, 3H), 7.54 (s, 1H), 7.68 (s, 1H), 8.42 (d,J=5.2 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 428 (M+1)⁺

Compound 3141-[2-(7-Hydroxy-6-methoxy-quinolin-4-yloxy)-4,5-dimethyl-phenyl]-ethanone

1-[2-(7-Benzyloxy-6-methoxy-quinolin-4-yloxy)-4,5-dimethyl-phenyl]-ethanone(compound 313) (1.10 g) was suspended in a mixed solution composed ofmethanesulfonic acid (0.8 ml) and trifluoroacetic acid (10 ml), and themixture was stirred at 70° C. for one hr. The solvent was removed bydistillation under the reduced pressure, water was added to the residue,and the mixture was neutralized with sodium hydrogencarbonate powder andwas then extracted with chloroform. Next, the chloroform layer waswashed with water and saturated brine and was dried over anhydrousmagnesium sulfate. The solvent was removed by distillation under thereduced pressure, and the residue was purified by column chromatographyusing chloroform-methanol to give the title compound (700 mg, yield83%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.29 (s, 3H), 2.33 (s, 3H), 2.45 (s, 3H),3.98 (s, 3H), 6.35 (d, J=5.2 Hz, 1H), 7.70 (s, 1H), 7.52 (s, 1H), 7.56(s, 1H), 7.72 (s, 1H), 8.45 (d, J=5.2 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 336 (M−1)⁻

Compound 3151-{2-[7-(2-Chloro-ethoxy)-6-methoxy-quinolin-4-yloxy]-4,5-dimethyl-phenyl}-ethanone

1-[2-(7-Hydroxy-6-methoxy-quinolin-4-yloxy)-4,5-dimethyl-phenyl]-ethanone(compound 314) (150 mg), 1-bromo-2-chloroethane (191 mg), and potassiumcarbonate (307 mg) were suspended in N,N-dimethylformamide (6 ml). Themixture was stirred at room temperature overnight, water was added tothe reaction solution, and the mixture was extracted with ethyl acetate.The ethyl acetate layer was then washed with water and saturated brineand was dried over anhydrous sodium sulfate. The solvent was removed bydistillation under the reduced pressure, and the residue was purified bycolumn chromatography using acetone-hexane to give the title compound(122 mg, 68%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.22 (s, 3H), 2.25 (s, 3H), 2.39 (s, 3H),3.88 (t, J=6.4 Hz, 2H), 3.95 (s, 3H), 4.38 (t, J=6.4 Hz, 2H), 6.33 (d,J=5.2 Hz, 1H), 6.85 (s, 1H), 7.35 (s, 1H), 7.50 (s, 1H), 7.64 (s, 1H),8.42 (d, J=5.2 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 400 (M+1)⁺

Compound 3161-{2-[6-Methoxy-7-(2-morpholin-4-yl-ethoxy)-quinolin-4-yloxy]-4,5-dimethyl-phenyl}-ethanone

1-{2-[7-(2-Chloro-ethoxy)-6-methoxy-quinolin-4-yloxy]-4,5-dimethyl-phenyl}-ethanone(compound 315) (52 mg), morpholine (34 mg), and potassium carbonate (90mg) were suspended in N,N-dimethylformamide (2 ml), and the suspensionwas stirred at 80° C. overnight. The reaction solution was cooled toroom temperature, water was then added to the reaction solution, and themixture was extracted with ethyl acetate. The ethyl acetate layer wasthen washed with water and saturated brine and was dried over anhydroussodium sulfate. The solvent was removed by distillation under thereduced pressure, and the residue was purified by thin layerchromatography using chloroform-methanol to give the title compound (18mg, 31%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.22 (s, 3H), 2.26 (s, 3H), 2.40 (s, 3H),2.57 (m, 4H), 2.88 (t, J=6.0 Hz, 2H), 3.68 (m, 4H), 3.94 (s, 3H), 4.26(t, J=6.0 Hz, 2H), 6.32 (d, J=5.2 Hz, 1H), 6.85 (s, 1H), 7.36 (s, 1H),7.49 (s, 1H), 7.65 (s, 1H), 8.41 (d, J=5.2 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 451 (M+1)⁺

Compound 3171-{2-[7-(2-Imidazol-1-yl-ethoxy)-6-methoxy-quinolin-4-yloxy]-4,5-dimethyl-phenyl}-ethanone

1-{2-[7-(2-Chloro-ethoxy)-6-methoxy-quinolin-4-yloxy]-4,5-dimethyl-phenyl}-ethanone(compound 315) (52 mg), imidazole (27 mg), and potassium carbonate (90mg) were suspended in N,N-dimethylformamide (2 ml), and the suspensionwas stirred at 80° C. overnight. The reaction solution was cooled toroom temperature, water was then added to the reaction solution, and themixture was extracted with ethyl acetate. The ethyl acetate layer wasthen washed with water and saturated brine and was dried over anhydroussodium sulfate. The solvent was removed by distillation under thereduced pressure, and the residue was purified by thin layerchromatography using chloroform-methanol to give the title compound (18mg, 31%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.22 (s, 3H), 2.25 (s, 3H), 2.39 (s, 3H),3.95 (s, 3H), 4.34 (m, 2H), 4.40 (m, 2H), 6.32 (d, J=5.2 Hz, 1H), 6.85(s, 1H), 7.00 (s, 1H), 7.07 (s, 1H), 7.29 (s, 1H), 7.49 (s, 1H), 7.64(m, 2H), 8.40 (d, J=5.2 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 432 (M+1)⁺

Compound 3181-{2-[7-(3-Chloro-propoxy)-6-methoxy-quinolin-4-yloxy]-4,5-dimethyl-phenyl}-ethanone

1-[2-(7-Hydroxy-6-methoxy-quinolin-4-yloxy)-4,5-dimethyl-phenyl]-ethanone(compound 314) (150 mg), 1-bromo-3-chloropropane (210 mg), and potassiumcarbonate (307 mg) were suspended in N,N-dimethylformamide (6 ml), andthe mixture was stirred at room temperature overnight. Water was addedto the reaction solution, and the mixture was extracted with ethylacetate. The ethyl acetate layer was then washed with water andsaturated brine and was dried over anhydrous sodium sulfate. The solventwas removed by distillation under the reduced pressure, and the residuewas purified by column chromatography using acetone-hexane to give thetitle compound (174 mg, 94%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.20 (s, 3H), 2.23 (s, 3H), 2.30 (m, 2H),2.38 (s, 3H), 3.70 (t, J=6.4 Hz, 2H), 3.92 (s, 3H), 4.25 (t, J=6.4 Hz,2H), 6.31 (d, J=5.2 Hz, 1H), 6.84 (s, 1H), 7.36 (s, 1H), 7.47 (s, 1H),7.63 (s, 1H), 8.40 (d, J=5.2 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 414 (M+1)⁺

Compound 3191-{2-[6-Methoxy-7-(3-morpholin-4-yl-propoxy)-quinolin-4-yloxy]-4,5-dimethyl-phenyl}-ethanone

1-{2-[7-(3-Chloro-propoxy)-6-methoxy-quinolin-4-yloxy]-4,5-dimethyl-phenyl}-ethanone(compound 318) (77 mg), morpholine (49 mg), and potassium carbonate (131mg) were suspended in N,N-dimethylformamide (2 ml), and the suspensionwas stirred at 80° C. overnight. The reaction solution was cooled toroom temperature, water was then added to the reaction solution, and themixture was extracted with ethyl acetate. The ethyl acetate layer wasthen washed with water and saturated brine and was dried over anhydroussodium sulfate. The solvent was removed by distillation under thereduced pressure, and the residue was purified by column chromatographyusing chloroform-methanol to give the title compound (60 mg, 68%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.05 (m, 2H), 2.21 (s, 3H), 2.25 (s, 3H),2.41 (m, 7H), 2.50 (t, J=7.2 Hz, 2H), 3.64 (m, 4H), 3.94 (s, 3H), 4.22(t, J=6.8 Hz, 2H), 6.32 (d, J=5.2 Hz, 1H), 6.85 (s, 1H), 7.35 (s, 1H),7.47 (s, 1H), 7.64 (s, 1H), 8.40 (d, J=5.2 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 465 (M+1)⁺

Compound 3201-{2-[6-Methoxy-7-(3-morpholin-4-yl-propoxy)-quinolin-4-yloxy]-4,5-dimethyl-phenyl}-ethanonehydrochloride

1-{2-[6-Methoxy-7-(3-morpholin-4-yl-propoxy)-quinolin-4-yloxy]-4,5-dimethyl-phenyl}-ethanone(compound 319) (344 mg) was dissolved in a hydrochloric acid-methanolsolution (10 ml), and the solution was stirred at room temperatureovernight. The solvent was removed by distillation under the reducedpressure, and the residue was washed with ethyl acetate and was driedunder the reduced pressure to give the title compound (398 mg, yield100%).

¹H-NMR (CD₃OD, 400 MHz): δ 2.25-2.55 (m, 11H), 3.22 (m, 2H), 3.49 (m,2H), 3.67 (d, J=12.0 Hz, 2H), 3.86 (t, J=12.0 Hz, 2H), 4.02-4.18 (m,5H), 4.47 (m, 2H), 6.76 (d, J=5.2 Hz, 1H), 7.22 (s, 1H), 7.52 (s, 1H),7.84 (s, 1H), 7.92 (s, 1H), 8.60 (d, J=5.2 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 465 (M+1-2HCl)⁺

Compound 3211-{2-[7-(3-Imidazol-1-yl-propoxy)-6-methoxy-quinolin-4-yloxy]-4,5-dimethyl-phenyl}-ethanone

1-{2-[7-(3-Chloro-propoxy)-6-methoxy-quinolin-4-yloxy]-4,5-dimethyl-phenyl}-ethanone(compound 318) (77 mg), imidazole (38 mg), and potassium carbonate (131mg) were suspended in N,N-dimethylformamide (2 ml), and the suspensionwas stirred at 80° C. overnight. The reaction solution was cooled toroom temperature, water was then added to the reaction solution, and themixture was extracted with ethyl acetate. The ethyl acetate layer wasthen washed with water and saturated brine and was dried over anhydroussodium sulfate. The solvent was removed by distillation under thereduced pressure, and the residue was purified by thin layerchromatography using chloroform-methanol to give the title compound (52mg, 61%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.22 (s, 3H), 2.25 (s, 3H), 2.30 (m, 2H),2.41 (s, 3H), 3.97 (s, 3H), 4.07 (t, J=6.4 Hz, 2H), 4.21 (t, J=6.4 Hz,2H), 6.32 (d, J=5.2 Hz, 1H), 6.85 (s, 1H), 6.88 (s, 1H), 6.97 (s, 1H),7.30 (s, 1H), 7.44 (s, 1H), 7.50 (s, 1H), 7.65 (s, 1H), 8.40 (d, J=5.2Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 446 (M+1)⁺

Compound 322 Propyl3-[7-(2-chloro-ethoxy)-6-methoxy-quinolin-4-yloxy]-naphthalene-2-carboxylate

3-Hydroxy-naphthalene-2-carboxylic acid (2 g) was dissolved in1-propanol (10 ml) to prepare a solution which was then brought to 0° C.Thionyl chloride (1.16 ml) was gradually added dropwise to the solution,and the mixture was stirred at 120° C. for 2 hr. The reaction solutionwas cooled to room temperature, and the solvent was removed bydistillation under the reduced pressure. Water was then added to theresidue, and the mixture was extracted with chloroform. The chloroformlayer was washed with saturated brine and was dried over anhydroussodium sulfate. The solvent was removed by distillation under thereduced pressure, and the residue was purified by column chromatographyusing chloroform to give propyl 3-hydroxy-naphthalene-2-carboxylate(2.15 g, yield 88%).

Propyl 3-hydroxy-naphthalene-2-carboxylate (460 mg),7-benzyloxy-4-chloro-6-methoxyquinoline (200 mg), and4-dimethylaminopyridine (244 mg) were suspended in o-dichlorobenzene (4ml), and the mixture was stirred at 120° C. for 5 hr. The reactionsolution was cooled to room temperature, water was then added to thereaction solution, and the mixture was extracted with chloroform. Thechloroform layer was washed with saturated brine and was dried overanhydrous sodium sulfate, the solvent was removed by distillation underthe reduced pressure, and the residue was purified by thin layerchromatography using chloroform-acetone to give propyl3-(7-benzyloxy-6-methoxy-quinolin-4-yloxy)-naphthalene-2-carboxylate(165 mg, yield 50%).

Propyl3-(7-benzyloxy-6-methoxy-quinolin-4-yloxy)-naphthalene-2-carboxylate(160 mg) was dissolved in trifluoroacetic acid (1.5 ml) to prepare asolution. Methanesulfonic acid (0.15 ml) was added to the solution, andthe mixture was stirred at 70° C. for one hr. The reaction solution wascooled to room temperature, and the solvent was removed by distillationunder the reduced pressure. An aqueous sodium hydrogencarbonate solutionwas then added to the residue, and the mixture was extracted withchloroform. The chloroform layer was washed with saturated brine and wasdried over anhydrous sodium sulfate. The solvent was removed bydistillation under the reduced pressure, and the residue was purified bythin layer chromatography using chloroform-acetone to give propyl3-(7-hydroxy-6-methoxy-quinolin-4-yloxy)-naphthalene-2-carboxylate (87mg, yield 68%).

Propyl3-(7-hydroxy-6-methoxy-quinolin-4-yloxy)-naphthalene-2-carboxylate (80mg) and 1-bromo-2-chloroethane (0.082 ml) were dissolved inN,N-dimethylformamide (2 ml) to prepare a solution. Potassium carbonate(274 mg) was added to the solution, and the mixture was stirred at roomtemperature overnight. Water was then added to the reaction solution,and the mixture was extracted with ethyl acetate. The ethyl acetatelayer was then washed with saturated brine and was dried over anhydroussodium sulfate. The solvent was removed by distillation under thereduced pressure, and the residue was purified by column chromatographyusing acetone-chloroform to give the title compound (85 mg, yield 91%).

¹H-NMR (CDCl₃, 400 MHz): δ 0.71 (t, J=7.3 Hz, 3H), 1.26-1.38 (m, 2H),3.97-4.05 (m, 4H), 4.07 (s, 3H), 4.50 (t, J=6.1 Hz, 2H), 6.37 (d, J=5.4Hz, 1H), 7.52-7.70 (m, 5H), 7.84 (d, J=8.3 Hz, 1H), 8.02 (d, J=8.1 Hz,1H), 8.44 (d, J=5.4 Hz, 1H), 8.67 (s, 1H)

Mass spectrometric value (ESI−MS, m/z): 466 (M+1)⁺

Compound 323 Propyl3-[6-methoxy-7-(2-morpholin-4-yl-ethoxy)-quinolin-4-yloxy]-naphthalene-2-carboxylate

Propyl3-[7-(2-chloro-ethoxy)-6-methoxy-quinolin-4-yloxy]-naphthalene-2-carboxylate(compound 322) (80 mg) was dissolved in N,N-dimethylformamide (2 ml) toprepare a solution. Potassium carbonate (484 mg) and morpholine (0.15ml) were added to the solution, and the mixture was stirred at 60° C.for 2 days. The reaction solution was cooled to room temperature, waterwas then added thereto, and the mixture was extracted with ethylacetate. The ethyl acetate layer was then washed with saturated brineand was dried over anhydrous sodium sulfate. The solvent was removed bydistillation under the reduced pressure, and the residue was purified bythin layer chromatography using hexane-acetone to give the titlecompound (52 mg, yield 59%).

¹H-NMR (CDCl₃, 400 MHz): δ 0.70-0.73 (m, 3H), 1.30-1.39 (m, 2H), 2.69(s, 4H), 2.98-3.01 (m, 2H), 3.79 (t, J=4.6 Hz, 4H), 4.02-4.04 (m, 2H),4.05 (s, 3H), 4.40 (t, J=5.9 Hz, 2H), 6.36 (d, J=5.6 Hz, 1H), 7.52-7.68(m, 5H), 7.84 (d, J=8.1 Hz, 1H), 8.02 (d, J=8.3 Hz, 1H), 8.43 (d, J=5.4Hz, 1H), 8.67 (s, 1H)

Mass spectrometric value (ESI−MS, m/z): 517 (M+1)⁺

Compound 324 Propyl3-[7-(2-imidazol-1-yl-ethoxy)-6-methoxy-quinolin-4-yloxy]-naphthalene-2-carboxylate

Propyl3-[7-(2-chloro-ethoxy)-6-methoxy-quinolin-4-yloxy]-naphthalene-2-carboxylate(compound 322) (138 mg) was dissolved in N,N-dimethylformamide (2 ml) toprepare a solution. Potassium carbonate (274 mg) and imidazole (101 mg)were added to the solution, and the mixture was stirred at 60° C.overnight. Water was added to the reaction solution, and the mixture wasextracted with ethyl acetate. The ethyl acetate layer was then washedwith saturated brine and was dried over anhydrous sodium sulfate. Thesolvent was removed by distillation under the reduced pressure, and theresidue was purified by thin layer chromatography usingchloroform-methanol to give the title compound (105 mg, yield 70%).

¹H-NMR (CDCl₃, 400 MHz): δ 0.71 (t, J=7.6 Hz, 3H), 1.30-1.39 (m, 2H),4.04 (t, J=6.6 Hz, 2H), 4.07 (s, 3H), 4.45-4.51 (m, 4H), 6.37 (d, J=5.4Hz, 1H), 7.10 (s, 1H), 7.17 (s, 1H), 7.52 (s, 1H), 7.58-7.69 (m, 4H),7.76 (s, 1H), 7.84 (d, J=8.1 Hz, 1H), 8.02 (d, J=8.1 Hz, 1H), 8.42 (d,J=5.6 Hz, 1H), 8.67 (s, 1H)

Mass spectrometric value (ESI−MS, m/z): 498 (M+1)⁺

Compound 325 Propyl3-[7-(3-chloro-propoxy)-6-methoxy-quinolin-4-yloxy]-naphthalene-2-carboxylate

Propyl3-(7-hydroxy-6-methoxy-quinolin-4-yloxy)-naphthalene-2-carboxylate (240mg) was dissolved in N,N-dimethylformamide (6 ml) to prepare a solution.Potassium carbonate (822 mg) and 1-bromo-3-chloropropane (0.29 ml) wereadded to the solution, and the mixture was stirred at room temperatureovernight. Water was added to the reaction solution, and the mixture wasextracted with ethyl acetate. The ethyl acetate layer was then washedwith saturated brine and was dried over anhydrous sodium sulfate. Thesolvent was removed by distillation under the reduced pressure, and theresidue was purified by thin layer chromatography usingacetone-chloroform to give the title compound (230 mg, yield 81%).

¹H-NMR (CDCl₃, 400 MHz): δ 0.71 (t, J=7.3 Hz, 3H), 1.30-1.39 (m, 2H),2.39-2.45 (m, 2H), 3.83 (t, J=6.3 Hz, 2H), 4.02-4.04 (m, 2H), 4.05 (s,3H), 4.39 (t, J=6.1 Hz, 2H), 6.35 (d, J=5.6 Hz, 1H), 7.56-7.68 (m, 5H),7.84 (d, J=8.1 Hz, 1H), 8.02 (d, J=8.1 Hz, 1H), 8.43 (d, J=5.4 Hz, 1H),8.67 (s, 1H)

Mass spectrometric value (ESI−MS, m/z): 480 (M+1)⁺

Compound 326 Propyl3-[6-methoxy-7-(3-morpholin-4-yl-propoxy)-quinolin-4-yloxy]-naphthalene-2-carboxylate

Propyl3-[7-(3-chloro-propoxy)-6-methoxy-quinolin-4-yloxy]-naphthalene-2-carboxylate(compound 325) (110 mg) was dissolved in N,N-dimethylformamide (3 ml) toprepare a solution. Potassium carbonate (317 mg) and morpholine (0.1 ml)were added to the solution, and the mixture was stirred at 60° C.overnight. Water was added to the reaction solution, the mixture wasextracted with chloroform, and the chloroform layer was then washed withsaturated brine and was dried over anhydrous sodium sulfate. The solventwas removed by distillation under the reduced pressure, and the residuewas purified by thin layer chromatography using chloroform-methanol togive the title compound (106 mg, yield 87%).

¹H-NMR (CDCl₃, 400 MHz): δ 0.70 (t, J=7.6 Hz, 3H), 1.29-1.38 (m, 2H),2.17-2.20 (m, 2H), 2.56-2.65 (m, 6H), 3.76-3.78 (m, 4H), 4.02-4.03 (m,2H), 4.05 (s, 3H), 4.30 (t, J=6.6 Hz, 2H), 6.33 (d, J=5.4 Hz, 1H), 7.50(s, 1H), 7.57-7.67 (m, 4H), 7.83 (d, J=7.8 Hz, 1H), 8.02 (d, J=8.1 Hz,1H), 8.43 (d, J=5.4 Hz, 1H), 8.66 (s, 1H)

Mass spectrometric value (ESI−MS, m/z): 531 (M+1)⁺

Compound 327 Propyl3-[7-(3-imidazol-1-yl-propoxy)-6-methoxy-quinolin-4-yloxy]-naphthalene-2-carboxylate

Propyl3-[7-(3-chloro-propoxy)-6-methoxy-quinolin-4-yloxy]-naphthalene-2-carboxylate(compound 325) (110 mg) was dissolved in N,N-dimethylformamide (3 ml) toprepare a solution. Potassium carbonate (317 mg) and imidazole (78 mg)were added to the solution, and the mixture was stirred at 60° C.overnight. Water was added to the reaction solution, and the mixture wasextracted with chloroform. The chloroform layer was then washed withsaturated brine and was dried over anhydrous sodium sulfate. The solventwas removed by distillation under the reduced pressure, and the residuewas purified by thin layer chromatography using chloroform-methanol togive the title compound (97 mg, yield 82%).

¹H-NMR (CDCl₃, 400 MHz): δ 0.73 (t, J=7.6 Hz, 3H), 1.32-1.41 (m, 2H),2.38-2.44 (m, 2H), 4.05 (t, J=6.6 Hz, 2H), 4.08 (s, 3H), 4.19 (t, J=5.9Hz, 2H), 4.29 (t, J=6.8 Hz, 2H), 6.36 (d, J=5.6 Hz, 1H), 6.98 (s, 1H),7.08 (s, 1H), 7.50 (s, 1H), 7.57-7.70 (m, 5H), 7.84 (d, J=8.1 Hz, 1H),8.02 (d, J=8.3 Hz, 1H), 8.43 (d, J=5.6 Hz, 1H), 8.67 (s, 1H)

Mass spectrometric value (ESI−MS, m/z): 512 (M+1)⁺

Compound 3287-Benzyloxy-6-methoxy-4-(6-methyl-2-thiazol-2-yl-pyridin-3-yloxy)-quinoline

2-Iodo-6-picolin-3-ol (10 g), 4-chloro-7-benzyloxy-6-methoxyquinoline(6.8 g), and 4-(N,N-dimethylamino)-pyridine (12.2 g) were dissolved in1,2-dichlorobenzene (400 ml) to prepare a solution, and the mixture wasstirred at 125° C. overnight. The reaction solution was cooled to roomtemperature, and the solvent was then removed by distillation under thereduced pressure. Water was added to the residue, the mixture wasextracted with chloroform, and the chloroform layer was then washed withwater and was dried over anhydrous sodium sulfate. The solvent wasremoved by distillation under the reduced pressure. The residue waspurified by column chromatography using chloroform-acetone to give7-benzyloxy-4-(2-iodo-6-methyl-pyridin-3-yloxy)-6-methoxy-quinoline (5.2g, yield 31%).

N,N-Dimethylformamide (2 ml) was added to7-benzyloxy-4-(2-iodo-6-methyl-pyridin-3-yloxy)-6-methoxy-quinoline (100mg), tetrakistriphenylphosphine palladium (23 mg),tri-n-butyl-(thiazol-2-yl)-tin (113 mg), and copper(II) oxide (32 mg)under an argon atmosphere, and the mixture was stirred at 100° C.overnight. The reaction solution was cooled to room temperature, waterwas then added thereto, and the mixture was extracted with ethylacetate. The ethyl acetate layer was then washed with water and wasdried over anhydrous sodium sulfate. The solvent was removed bydistillation under the reduced pressure, and the residue was purified bycolumn chromatography using hexane-acetone to give the title compound(43 mg, yield 46%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.63 (s, 3H), 3.96 (s, 3H), 5.25 (s, 2H),6.29 (d, J=5.4 Hz, 1H), 7.17-7.48 (m, 9H), 7.62 (s, 1H), 7.74 (d, J=3.2Hz, 1H), 8.34 (d, J=5.4 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 478 (M+Na)⁺

Compound 3296-Methoxy-4-(6-methyl-2-thiazol-2-yl-pyridin-3-yloxy)-quinolin-7-ol

Trifluoroacetic acid (1 ml) and methanesulfonic acid (0.1 ml) were addedto7-benzyloxy-6-methoxy-4-(6-methyl-2-thiazol-2-yl-pyridin-3-yloxy)-quinoline(compound 328) (40 mg), and the mixture was stirred at 80° C. for 1.5hr. The reaction solution was cooled to room temperature, and asaturated aqueous sodium hydrogencarbonate solution was then added tothe reaction solution. The mixture was made alkaline, and the mixturewas then extracted with chloroform. The chloroform layer was washed withwater and was dried over anhydrous sodium sulfate. The solvent wasremoved by distillation under the reduced pressure, and the residue waspurified by thin layer chromatography using chloroform-methanol to givethe title compound (23 mg, yield 70%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.70 (s, 3H), 4.06 (s, 3H), 6.35 (d, J=5.4Hz, 1H), 7.28 (d, J=8.3 Hz, 1H), 7.34 (d, J=3.2 Hz, 1H), 7.48 (d, J=8.3Hz, 1H), 7.57 (s, 1H), 7.69 (s, 1H), 7.79 (d, J=3.2 Hz, 1H), 8.43 (d,J=5.4 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 388 (M+Na)⁺

Compound 3302-[6-Methoxy-4-(6-methyl-2-thiazol-2-yl-pyridin-3-yloxy)-quinolin-7-yloxymethyl]-propane-1,3-diol

A solution of 2-methoxypropene (1 g) in N,N-dimethylformamide (150 ml)was added to 2-(hydroxymethyl)-1,3-propanediol (500 mg).p-Toluenesulfonic acid (10 mg) was added thereto, and the mixture wasstirred at room temperature overnight. The solvent was removed bydistillation under the reduced pressure, water was added to the residue,and the mixture was extracted with n-butanol. The n-butanol layer wasthen washed with water and was dried over anhydrous sodium sulfate. Thesolvent was removed by distillation under the reduced pressure, and theresidue was purified by column chromatography using hexane-acetone togive (2,2-dimethyl[1,3]dioxan-5-yl)-methanol (378 mg, yield 55%).

Toluene (0.4 ml) was added to6-methoxy-4-(6-methyl-2-thiazol-2-yl-pyridin-3-yloxy)-quinolin-7-ol(compound 329) (20 mg) and (2,2-dimethyl[1,3]dioxan-5-yl)-methanol (24mg). Triphenylphosphine (43 mg) and a solution of diethylazocarbodiimide(29 mg) in toluene (0.2 ml) were added in that order to the mixture, andthe mixture was stirred at room temperature for 4 hr. A 1 N aqueoussulfuric acid solution (1 ml) was added to the reaction solution, andthe mixture was stirred at room temperature overnight. Water was addedto the reaction solution, the mixture was washed with ethyl acetate, andthe ethyl acetate layer was extracted with 1 N hydrochloric acid.Aqueous layers were combined, the combined aqueous layers were madealkaline by the addition of potassium carbonate, and the mixture wasextracted with ethyl acetate. The ethyl acetate layer was washed withwater and was dried over anhydrous sodium sulfate. The solvent wasremoved by distillation under the reduced pressure, and the residue waspurified by thin layer chromatography using chloroform-methanol to givethe title compound (4.7 mg, yield 19%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.34-2.47 (m, 1H), 2.63 (s, 3H), 3.96-4.05(m, 7H), 4.41 (d, J=5.6 Hz, 2H), 6.38 (d, J=5.1 Hz, 1H), 7.30 (d, J=8.3Hz, 1H), 7.36 (d, J=3.2 Hz, 1H), 7.47 (s, 1H), 7.50 (d, J=8.6 Hz, 1H),7.67 (s, 1H), 7.81 (d, J=3.2 Hz, 1H), 8.43 (d, J=5.1 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 454 (M+1)⁺

Compound 3317-Benzyloxy-4-(5,6-dimethyl-2-phenyl-pyridin-3-yloxy)-6-methoxy-quinoline

5,6-Dimethyl-2-phenyl-pyridin-3-ol (400 mg),7-benzyloxy-4-chloro-6-methoxyquinoline (1.81 g), and4-dimethylaminopyridine (736 mg) were suspended in o-dichlorobenzene (10ml), and the suspension was stirred at 140° C. for 4 hr. The reactionsolution was cooled to room temperature, water was then added to thereaction solution, and the mixture was extracted with chloroform. Thechloroform layer was washed with saturated brine and was dried overanhydrous sodium sulfate. The solvent was removed by distillation underthe reduced pressure, and the residue was purified by columnchromatography using chloroform-methanol to give the title compound (965mg, yield 100%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.35 (s, 3H), 2.62 (s, 3H), 4.02 (s, 3H),5.31 (s, 2H), 6.37 (d, J=5.4 Hz, 1H), 7.25-7.52 (m, 11H), 7.82-7.85 (m,2H), 8.40 (d, J=5.4 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 463 (M+1)⁺

Compound 3324-(5,6-Dimethyl-2-phenyl-pyridin-3-yloxy)-6-methoxy-quinolin-7-ol

7-Benzyloxy-4-(5,6-dimethyl-2-phenyl-pyridin-3-yloxy)-6-methoxy-quinoline(compound 331) (958 mg) was dissolved in trifluoroacetic acid (9.5 ml)to prepare a solution. Methanesulfonic acid (0.95 ml) was added to thesolution, and the mixture was stirred at 70° C. for one hr. The reactionsolution was cooled to room temperature, and the solvent was removed bydistillation under the reduced pressure. An aqueous sodiumhydrogencarbonate solution was then added to the residue, and themixture was extracted with chloroform. The chloroform layer was washedwith saturated brine and was dried over anhydrous sodium sulfate. Thesolvent was removed by distillation under the reduced pressure, and theresidue was purified by column chromatography using chloroform-methanolto give the title compound (848 mg, yield 100%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.35 (s, 3H), 2.62 (s, 3H), 4.04 (s, 3H),6.37 (d, J=5.1 Hz, 1H), 7.25-7.31 (m, 4H), 7.52 (d, J=4.4 Hz, 2H),7.82-7.85 (m, 2H), 8.44 (d, J=5.1 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 373 (M+1)⁺

Compound 3332-[4-(5,6-Dimethyl-2-phenyl-pyridin-3-yloxy)-6-methoxy-quinolin-7-yloxy]-ethanol

4-(5,6-Dimethyl-2-phenyl-pyridin-3-yloxy)-6-methoxy-quinolin-7-ol(compound 332) (162 mg) was dissolved in N,N-dimethylformamide (3 ml) toprepare a solution. Potassium carbonate (180 mg) and 2-bromoethanol (0.1ml) were added to the solution, and the mixture was stirred at 70° C.overnight. The solvent was removed by distillation under the reducedpressure, water was then added to the residue, and the mixture wasextracted with chloroform. The chloroform layer was washed withsaturated brine and was dried over anhydrous sodium sulfate. The solventwas removed by distillation under the reduced pressure, and the residuewas purified by thin layer chromatography using chloroform-acetone togive the title compound (135 mg, yield 76%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.36 (s, 3H), 2.63 (s, 3H), 4.00 (s, 3H),4.09 (t, J=4.4 Hz, 2H), 4.29 (t, J=4.9 Hz, 2H), 6.39 (d, J=5.4 Hz, 1H),7.24-7.29 (m, 4H), 7.44 (s, 1H), 7.51 (s, 1H), 7.82-7.85 (m, 2H), 8.42(d, J=5.4 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 417 (M+1)⁺

Compound 3344-(5,6-Dimethyl-2-phenyl-pyridin-3-yloxy)-6-methoxy-7-oxiranylmethoxy-quinoline

4-(5,6-Dimethyl-2-phenyl-pyridin-3-yloxy)-6-methoxy-quinolin-7-ol(compound 332) (150 mg) was dissolved in N,N-dimethylformamide (4 ml) toprepare a solution, potassium carbonate (167 mg) and epibromohydrin (0.1ml) were added to the solution, and the mixture was stirred at roomtemperature overnight. Water was added to the reaction solution, and themixture was extracted with ethyl acetate. The ethyl acetate layer wasthen washed with saturated brine and was dried over anhydrous sodiumsulfate. The solvent was removed by distillation under the reducedpressure, and the residue was purified by thin layer chromatographyusing chloroform-methanol to give the title compound (140 mg, yield82%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.35 (s, 3H), 2.62 (s, 3H), 2.84 (dd, J=2.7Hz, 4.9 Hz, 1H), 2.95-2.97 (m, 1H), 3.48-3.52 (m, 1H), 4.01 (s, 3H),4.17 (dd, J=5.6 Hz, 11.2 Hz, 1H), 4.42 (dd, J=3.2 Hz, 11.2 Hz, 1H), 6.38(d, J=5.1 Hz, 1H), 7.22-7.30 (m, 4H), 7.41 (s, 1H), 7.51 (s, 1H),7.82-7.85 (m, 2H), 8.42 (d, J=5.1 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 429 (M+1)⁺

Compound 3353-[4-(5,6-Dimethyl-2-phenyl-pyridin-3-yloxy)-6-methoxy-quinolin-7-yloxy]-propane-1,2-diol

4-(5,6-Dimethyl-2-phenyl-pyridin-3-yloxy)-6-methoxy-7-oxiranylmethoxy-quinoline(compound 334) (130 mg) was dissolved in methylene chloride (2 ml) toprepare a solution which was then brought to 0° C. Trifluoroacetic acid(1 ml) was added to the solution, and the mixture was stirred at 0° C.for 30 min and was then stirred at room temperature for 3 hr. Thereaction solution was brought to 0° C., was stirred, and was madealkaline by the addition of a 10% aqueous sodium hydroxide solution.Water was added to the reaction solution, and the mixture was extractedwith chloroform. The chloroform layer was then washed with saturatedbrine and was dried over anhydrous sodium sulfate. The solvent wasremoved by distillation under the reduced pressure, and the residue waspurified by thin layer chromatography using chloroform-methanol to givethe title compound (89 mg, yield 66%).

¹H-NMR (CD₃OD, 400 MHz): δ 2.41 (s, 3H), 2.60 (s, 3H), 3.69-3.78 (m,2H), 3.99 (s, 3H), 4.08-4.16 (m, 2H), 4.21-4.25 (m, 1H), 6.38 (d, J=5.4Hz, 1H), 7.24-7.31 (m, 4H), 7.56 (d, J=3.4 Hz, 2H), 7.69-7.72 (m, 2H),8.30 (d, J=5.4 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 447 (M+1)⁺

Compound 3362-[4-(5,6-Dimethyl-2-phenyl-pyridin-3-yloxy)-6-methoxy-quinolin-7-yloxymethyl]-propane-1,3-diol

4-(5,6-Dimethyl-2-phenyl-pyridin-3-yloxy)-6-methoxy-quinolin-7-ol(compound 332) (85 mg) was dissolved in tetrahydrofuran (2 ml) toprepare a solution. Triphenylphosphine (120 mg),(2,2-dimethyl-[1,3]dioxan-5-yl)-methanol (40 mg), anddiethylazodicarboxylic acid (0.083 ml) were added to the solution, andthe mixture was stirred at room temperature for 4 hr. Further, 1 Nsulfuric acid (4 ml) was added thereto, and the mixture was stirred atroom temperature overnight. The reaction solution was brought to 0° C.,was stirred, and was made alkaline by the addition of a 10% aqueoussodium hydroxide solution. Water was added thereto, and the mixture wasextracted with ethyl acetate. The ethyl acetate layer was then washedwith saturated brine and was dried over anhydrous sodium sulfate. Thesolvent was removed by distillation under the reduced pressure, and theresidue was purified by thin layer chromatography usingchloroform-methanol to give the title compound (80 mg, yield 76%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.35-2.40 (m, 4H), 2.63 (s, 3H), 3.94-4.02(m, 7H), 4.38 (d, J=5.6 Hz, 2H), 6.38 (d, J=5.4 Hz, 1H), 7.22-7.30 (m,4H), 7.43 (s, 1H), 7.47 (s, 1H), 7.82-7.84 (m, 2H), 8.41 (d, J=5.4 Hz,1H)

Mass spectrometric value (ESI−MS, m/z): 461 (M+1)⁺

Compound 3373-(7-Benzyloxy-6-methoxy-quinolin-4-yloxy)-5,6-dimethyl-[2,2′]bipyridine

5,6-Dimethyl-3-hydroxy-[2,2′]bipyridine (241 mg),7-benzyloxy-4-chloro-6-methoxyquinoline (1.08 g),4-dimethylaminopyridine (441 mg), and cesium carbonate (1.18 g) weresuspended in dimethyl sulfoxide (6 ml), and the mixture was stirred at130° C. overnight. The reaction solution was cooled to room temperature,water was then added to the reaction solution, and the mixture wasextracted with chloroform. The chloroform layer was washed withsaturated brine and was dried over anhydrous sodium sulfate. The solventwas removed by distillation under the reduced pressure, and the residuewas purified by column chromatography using chloroform-methanol to givethe title compound (408 mg, yield 73%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.38 (s, 3H), 2.66 (s, 3H), 4.02 (s, 3H),5.31 (s, 2H), 6.37 (d, J=5.4 Hz, 1H), 7.10-7.13 (m, 1H), 7.25-7.61 (m,9H), 7.80 (d, J=7.8 Hz, 1H), 8.37 (d, J=5.4 Hz, 1H), 8.51 (d, J=4.4 Hz,1H)

Mass spectrometric value (ESI−MS, m/z): 464 (M+1)⁺

Compound 3384-(5,6-Dimethyl-[2,2′]bipyridin-3-yloxy)-6-methoxy-quinolin-7-ol

3-(7-Benzyloxy-6-methoxy-quinolin-4-yloxy)-5,6-dimethyl-[2,2′]bipyridine(compound 337) (497 mg) was dissolved in trifluoroacetic acid (5 ml) toprepare a solution. Methanesulfonic acid (0.5 ml) was added to thesolution, and the mixture was stirred at 70° C. for 1.5 hr. The reactionsolution was cooled to room temperature, and the solvent was removed bydistillation under the reduced pressure. An aqueous sodiumhydrogencarbonate solution was then added to the residue, and themixture was extracted with chloroform. The chloroform layer was washedwith saturated brine and was dried over anhydrous sodium sulfate. Thesolvent was removed by distillation under the reduced pressure, and theresidue was purified by thin layer chromatography usingchloroform-methanol to give the title compound (437 mg, yield 100%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.38 (s, 3H), 2.65 (s, 3H), 4.05 (s, 3H),6.36 (d, J=5.4 Hz, 1H), 7.11-7.14 (m, 1H), 7.35 (s, 1H), 7.52 (s, 1H),7.57-7.62 (m, 2H), 7.78-7.81 (m, 1H), 8.40 (d, J=5.4 Hz, 1H), 8.49-8.52(m, 1H)

Mass spectrometric value (ESI−MS, m/z): 374 (M+1)⁺

Compound 3392-[4-(5,6-Dimethyl-[2,2′]bipyridin-3-yloxy)-6-methoxy-quinolin-7-yloxy]-ethanol

4-(5,6-Dimethyl-[2,2′]bipyridin-3-yloxy)-6-methoxy-quinolin-7-ol(compound 338) (80 mg) was dissolved in N,N-dimethylformamide (2 ml) toprepare a solution. Potassium carbonate (89 mg) and 2-bromoethanol (0.05ml) were added to the solution, and the mixture was stirred at 70° C.overnight. The solvent was removed by distillation under the reducedpressure, water was then added to the residue, and the mixture wasextracted with chloroform. The chloroform layer was washed withsaturated brine and was dried over anhydrous sodium sulfate, the solventwas removed by distillation under the reduced pressure, and the residuewas purified by thin layer chromatography using chloroform-methanol togive the title compound (77 mg, yield 88%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.39 (s, 3H), 2.66 (s, 3H), 4.00 (s, 3H),4.08 (t, J=4.4 Hz, 2H), 4.29 (t, J=4.6 Hz, 2H), 6.38 (dd, J=0.5 Hz, 5.4Hz, 1H), 7.10-7.13 (m, 1H), 7.37 (s, 1H), 7.43 (s, 1H), 7.56 (s, 1H),7.57-7.61 (m, 1H), 7.81 (dd, J=1.0 Hz, 8.1 Hz, 1H), 8.39 (d, J=5.4 Hz,1H), 8.48-8.49 (m, 1H)

Mass spectrometric value (ESI−MS, m/z): 418 (M+1)⁺

Compound 3403-[4-(5,6-Dimethyl-[2,2′]bipyridin-3-yloxy)-6-methoxy-quinolin-7-yloxy]-propan-1-ol

4-(5,6-Dimethyl-[2,2′]bipyridin-3-yloxy)-6-methoxy-quinolin-7-ol(compound 338) (45 mg) was suspended in N,N-dimethylformamide (5 ml),potassium carbonate (50 mg) and 3-bromo-1-propanol (0.03 ml) were addedto the suspension, and the mixture was stirred at room temperatureovernight. The solvent was removed by distillation under the reducedpressure, water was then added to the residue, and the mixture wasextracted with chloroform. The chloroform layer was washed withsaturated brine and was dried over anhydrous sodium sulfate. The solventwas removed by distillation under the reduced pressure, and the residuewas purified by thin layer chromatography using chloroform-acetone togive the title compound (22 mg, yield 42%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.16-2.22 (m, 2H), 2.39 (s, 3H), 2.66 (s,3H), 3.93 (t, J=5.4 Hz, 2H), 4.00 (s, 3H), 4.38 (t, J=6.1 Hz, 2H), 6.38(d, J=5.4 Hz, 1H), 7.10-7.13 (m, 1H), 7.37 (s, 1H), 7.44 (s, 1H), 7.54(s, 1H), 7.57-7.61 (m, 1H), 7.81 (d, J=7.8 Hz, 1H), 8.38 (d, J=5.4 Hz,1H), 8.47-8.49 (m, 1H)

Mass spectrometric value (ESI−MS, m/z): 432 (M+1)⁺

Compound 3413-(6-Methoxy-7-oxiranylmethoxy-quinolin-4-yloxy)-5,6-dimethyl-[2,2′]bipyridine

4-(5,6-Dimethyl-[2,2′]bipyridin-3-yloxy)-6-methoxy-quinolin-7-ol(compound 338) (97 mg) was dissolved in N,N-dimethylformamide (4 ml),potassium carbonate (107 mg) and epibromohydrin (0.07 ml) were added tothe solution, and the mixture was stirred at room temperature overnight.The solvent was removed by distillation under the reduced pressure,water was then added to the residue, and the mixture was extracted withchloroform. The chloroform layer was washed with saturated brine and wasdried over anhydrous sodium sulfate. The solvent was removed bydistillation under the reduced pressure, and the residue was purified bythin layer chromatography using chloroform-methanol to give the titlecompound (99 mg, yield 89%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.39 (s, 3H), 2.66 (s, 3H), 2.84 (dd, J=2.4Hz, 4.9 Hz, 1H), 2.95-2.97 (m, 1H), 3.48-3.52 (m, 1H), 4.02 (s, 3H),4.17 (dd, J=5.6 Hz, 11.2 Hz, 1H), 4.43 (dd, J=3.2 Hz, 11.2 Hz, 1H), 6.38(d, J=5.1 Hz, 1H), 7.10-7.13 (m, 1H), 7.37 (s, 1H), 7.41 (s, 1H), 7.56(s, 1H), 7.56-7.61 (m, 1H), 7.80 (d, J=8.1 Hz, 1H), 8.39 (d, J=5.4 Hz,1H), 8.48-8.50 (m, 1H)

Mass spectrometric value (ESI−MS, m/z): 430 (M+1)⁺

Compound 3423-[4-(5,6-Dimethyl-[2,2′]bipyridin-3-yloxy)-6-methoxy-quinolin-7-yloxy]-propane-1,2-diol

3-(6-Methoxy-7-oxiranylmethoxy-quinolin-4-yloxy)-5,6-dimethyl-[2,2′]bipyridine(compound 341) (95 mg) was dissolved in methylene chloride (2 ml) toprepare a solution which was then brought to 0° C. Trifluoroacetic acid(1 ml) was added to the solution, the mixture was stirred at 0° C. for30 min, and the mixture was then stirred at room temperature for 5 hr.The reaction solution was brought to 0° C., was stirred, and was madealkaline by the addition of a 10% aqueous sodium hydroxide solution.Water was added thereto, the mixture was extracted with chloroform, andthe chloroform layer was then washed with saturated brine and was driedover anhydrous sodium sulfate. The solvent was removed by distillationunder the reduced pressure, and the residue was purified by thin layerchromatography using chloroform-methanol to give the title compound (63mg, yield 64%).

¹H-NMR (CD₃OD, 400 MHz): δ 2.45 (s, 3H), 2.63 (s, 3H), 3.69-3.77 (m,2H), 4.02 (s, 3H), 4.06-4.15 (m, 2H), 4.20-4.24 (m, 1H), 6.36 (d, J=5.4Hz, 1H), 7.23-7.26 (m, 1H), 7.28 (s, 1H), 7.64 (s, 1H), 7.65 (s, 1H),7.72-7.82 (m, 2H), 8.27 (d, J=5.4 Hz, 1H), 8.39 (d, J=4.9 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 448 (M+1)⁺

Compound 3432-[4-(5,6-Dimethyl-[2,2′]bipyridin-3-yloxy)-6-methoxy-quinolin-7-yloxymethyl]-propane-1,3-diol

4-(5,6-Dimethyl-[2,2′]bipyridin-3-yloxy)-6-methoxy-quinolin-7-ol(compound 338) (80 mg) was dissolved in tetrahydrofuran (2 ml) toprepare a solution. Triphenylphosphine (112 mg),(2,2-dimethyl-[1,3]dioxan-5-yl)-methanol (38 mg), anddiethylazodicarboxylate (0.078 ml) were added to the solution, and themixture was stirred at room temperature for 6 hr. Further, 1 N sulfuricacid (4 ml) was added thereto, the mixture was stirred at roomtemperature overnight, and the reaction solution was brought to 0° C.and was stirred. The reaction solution was made alkaline by the additionof a 10% aqueous sodium hydroxide solution. Water was added thereto, andthe mixture was extracted with ethyl acetate. The ethyl acetate layerwas then washed with saturated brine and was dried over anhydrous sodiumsulfate. The solvent was removed by distillation under the reducedpressure, and the residue was purified by thin layer chromatographyusing chloroform-methanol to give the title compound (50 mg, yield 52%).

¹H-NMR (CD₃OD, 400 MHz): δ 2.25-2.28 (m, 1H), 2.45 (s, 3H), 2.63 (s,3H), 3.80 (d, J=5.9 Hz, 4H), 4.01 (s, 3H), 4.24 (d, J=5.9 Hz, 2H), 6.35(d, J=5.6 Hz, 1H), 7.23-7.27 (m, 1H), 7.29 (s, 1H), 7.64 (s, 2H),7.73-7.81 (m, 2H), 8.26 (d, J=5.4 Hz, 1H), 8.39-8.41 (m, 1H)

Mass spectrometric value (ESI−MS, m/z): 462 (M+1)⁺

Compound 3443-(7-Benzyloxy-6-methoxy-quinolin-4-yloxy)-5,6-dimethyl-[2,3′]bipyridine

5,6-Dimethyl-3-hydroxy-[2,3′]bipyridine (400 mg),7-benzyloxy-4-chloro-6-methoxyquinoline (1.80 g), and4-dimethylaminopyridine (732 mg) were suspended in o-dichlorobenzene (8ml), and the suspension was stirred at 140° C. for 6 hr. The reactionsolution was cooled to room temperature, water was then added to thereaction solution, and the mixture was extracted with chloroform. Thechloroform layer was washed with saturated brine and was dried overanhydrous sodium sulfate. The solvent was removed by distillation underthe reduced pressure, and the residue was purified by columnchromatography using chloroform-methanol to give the title compound (811mg, yield 88%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.36 (s, 3H), 2.63 (s, 3H), 4.03 (s, 3H),5.32 (s, 2H), 6.36 (d, J=5.4 Hz, 1H), 7.22-7.52 (m, 9H), 8.15-8.18 (m,1H), 8.41 (d, J=5.4 Hz, 1H), 8.50 (dd, J=1.7 Hz, 4.9 Hz, 1H), 9.13-9.16(m, 1H)

Mass spectrometric value (ESI−MS, m/z): 464 (M+1)⁺

Compound 3454-(5,6-Dimethyl-[2,3′]bipyridin-3-yloxy)-6-methoxy-quinolin-7-ol

3-(7-Benzyloxy-6-methoxy-quinolin-4-yloxy)-5,6-dimethyl-[2,3′]bipyridine(compound 344) (804 mg) was dissolved in trifluoroacetic acid (8 ml) toprepare a solution. Methanesulfonic acid (0.8 ml) was added to thesolution, and the mixture was stirred at 70° C. for 1.5 hr. The reactionsolution was cooled to room temperature, and the solvent was removed bydistillation under the reduced pressure. An aqueous sodiumhydrogencarbonate solution was then added to the residue, and themixture was extracted with chloroform. The chloroform layer was washedwith saturated brine and was dried over anhydrous sodium sulfate. Thesolvent was removed by distillation under the reduced pressure, and theresidue was purified by column chromatography using chloroform-methanolto give the title compound (777 mg, yield 100%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.37 (s, 3H), 2.64 (s, 3H), 4.01 (s, 3H),6.34 (d, J=5.4 Hz, 1H), 7.25-7.30 (m, 1H), 7.32 (s, 1H), 7.49 (s, 2H),8.18-8.21 (m, 1H), 8.43 (d, J=5.4 Hz, 1H), 8.50 (dd, J=1.5 Hz, 4.6 Hz,1H), 9.16 (dd, J=1.0 Hz, 2.2 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 374 (M+1)⁺

Compound 3462-[4-(5,6-Dimethyl-[2,3′]bipyridin-3-yloxy)-6-methoxy-quinolin-7-yloxy]-ethanol

4-(5,6-Dimethyl-[2,3′]bipyridin-3-yloxy)-6-methoxy-quinolin-7-ol(compound 345) (150 mg) was dissolved in N,N-dimethylformamide (4 ml) toprepare a solution. Potassium carbonate (167 mg) and 2-bromoethanol(0.09 ml) were added to the solution, and the mixture was stirred at 70°C. overnight. The solvent was removed by distillation under the reducedpressure, water was then added to the residue, and the mixture wasextracted with chloroform. The chloroform layer was washed withsaturated brine and was dried over anhydrous sodium sulfate. The solventwas removed by distillation under the reduced pressure, and the residuewas purified by thin layer chromatography using chloroform-acetone togive the title compound (132 mg, yield 79%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.37 (s, 3H), 2.64 (s, 3H), 4.01 (s, 3H),4.09 (t, J=4.4 Hz, 2H), 4.30 (t, J=4.9 Hz, 2H), 6.38 (d, J=5.4 Hz, 1H),7.22-7.25 (m, 1H), 7.32 (s, 1H), 7.45 (s, 1H), 7.49 (s, 1H), 8.15-8.18(m, 1H), 8.44 (d, J=5.4 Hz, 1H), 8.50 (dd, J=1.7 Hz, 6.6 Hz, 1H), 9.14(dd, J=0.7 Hz, 2.2 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 418 (M+1)⁺

Compound 3473-[4-(5,6-Dimethyl-[2,3′]bipyridin-3-yloxy)-6-methoxy-quinolin-7-yloxy]-propan-1-ol

4-(5,6-Dimethyl-[2,3′]bipyridin-3-yloxy)-6-methoxy-quinolin-7-ol(compound 345) (45 mg) was dissolved in N,N-dimethylformamide (2 ml) toprepare a solution, potassium carbonate (50 mg) and 3-bromo-1-propanol(0.03 ml) were added to the solution, and the mixture was stirred atroom temperature overnight. The solvent was removed by distillationunder the reduced pressure, water was then added to the residue, and themixture was extracted with chloroform. The chloroform layer was washedwith saturated brine and was dried over anhydrous sodium sulfate. Thesolvent was removed by distillation under the reduced pressure, and theresidue was purified by thin layer chromatography usingchloroform-acetone to give the title compound (13 mg, yield 24%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.16-2.22 (m, 2H), 2.37 (s, 3H), 2.64 (s,3H), 3.93 (t, J=5.6 Hz, 2H), 4.01 (s, 3H), 4.38 (t, J=6.1 Hz, 2H), 6.38(d, J=5.4 Hz, 1H), 7.22-7.25 (m, 1H), 7.32 (s, 1H), 7.47 (s, 1H), 7.48(s, 1H), 8.15-8.18 (m, 1H), 8.43 (d, J=5.4 Hz, 1H), 8.50 (dd, J=1.7 Hz,4.9 Hz, 1H), 9.13 (d, J=1.7 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 432 (M+1)⁺

Compound 3483-(6-Methoxy-7-oxiranylmethoxy-quinolin-4-yloxy)-5,6-dimethyl-[2,3′]bipyridine

4-(5,6-Dimethyl-[2,3′]bipyridin-3-yloxy)-6-methoxy-quinolin-7-ol(compound 345) (146 mg) was dissolved in N,N-dimethylformamide (4 ml) toprepare a solution, potassium carbonate (162 mg) and epibromohydrin (0.1ml) were added to the solution, and the mixture was stirred at roomtemperature overnight. Water was added to the reaction solution, and themixture was extracted with ethyl acetate. The ethyl acetate layer wasthen washed with saturated brine and was dried over anhydrous sodiumsulfate. The solvent was removed by distillation under the reducedpressure, and the residue was purified by thin layer chromatographyusing chloroform-methanol to give the title compound (98 mg, yield 59%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.37 (s, 3H), 2.63 (s, 3H), 2.83-2.85 (m,1H), 2.95-2.97 (m, 1H), 3.48-3.52 (m, 1H), 4.02 (s, 3H), 4.18 (dd, J=5.6Hz, 11.2 Hz, 1H), 4.43 (dd, J=3.2 Hz, 11.2 Hz, 1H), 6.37 (d, J=5.1 Hz,1H), 7.22-7.29 (m, 1H), 7.31 (s, 1H), 7.43 (s, 1H), 7.49 (s, 1H),8.15-8.18 (m, 1H), 8.44 (d, J=5.4 Hz, 1H), 8.50 (dd, J=1.7 Hz, 4.9 Hz,1H), 9.14 (d, J=2.2 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 430 (M+1)⁺

Compound 3493-[4-(5,6-Dimethyl-[2,3′]bipyridin-3-yloxy)-6-methoxy-quinolin-7-yloxy]-propane-1,2-diol

3-(6-Methoxy-7-oxiranylmethoxy-quinolin-4-yloxy)-5,6-dimethyl-[2,3′]bipyridine(compound 348) (92 mg) was dissolved in methylene chloride (2 ml) toprepare a solution which was then brought to 0° C. Trifluoroacetic acid(1 ml) was added to the solution, and the mixture was stirred at 0° C.for 30 min. The mixture was then stirred at room temperature for 5 hr.The reaction solution was brought to 0° C., was stirred, and was madealkaline by the addition of a 10% aqueous sodium hydroxide solution.Water was added, and the mixture was extracted with chloroform. Thechloroform layer was then washed with saturated brine and was dried overanhydrous sodium sulfate. The solvent was removed by distillation underthe reduced pressure, and the residue was purified by thin layerchromatography using chloroform-methanol to give the title compound (34mg, yield 36%).

¹H-NMR (CD₃OD, 400 MHz): δ 2.42 (s, 3H), 2.63 (s, 3H), 3.69-3.78 (m,2H), 4.02 (s, 3H), 4.06-4.16 (m, 2H), 4.22-4.25 (m, 1H), 6.41 (d, J=5.4Hz, 1H), 7.33 (s, 1H), 7.35-7.38 (m, 1H), 7.60 (s, 1H), 7.62 (s, 1H),8.24-8.27 (m, 1H), 8.33 (d, J=5.4 Hz, 1H), 8.39 (dd, J=1.7 Hz, 4.9 Hz,1H), 8.97-8.98 (m, 1H)

Mass spectrometric value (ESI−MS, m/z): 470 (M+Na)⁺

Compound 3502-[4-(5,6-Dimethyl-[2,3′]bipyridin-3-yloxy)-6-methoxy-quinolin-7-yloxymethyl]-propane-1,3-diol

4-(5,6-Dimethyl-[2,3′]bipyridin-3-yloxy)-6-methoxy-quinolin-7-ol(compound 345) (80 mg) was dissolved in tetrahydrofuran (2 ml) toprepare a solution. Triphenylphosphine (112 mg),(2,2-dimethyl-[1,3]dioxan-5-yl)-methanol (38 mg), anddiethylazodicarboxylate (0.078 ml) were added to the solution, and themixture was stirred at room temperature for 6 hr. Further, 1 N sulfuricacid (4 ml) was added thereto, and the mixture was stirred at roomtemperature overnight. The reaction solution was brought to 0° C., wasstirred, and was made alkaline by the addition of a 10% aqueous sodiumhydroxide solution. Water was added thereto, and the mixture wasextracted with ethyl acetate. The ethyl acetate layer was then washedwith saturated brine and was dried over anhydrous sodium sulfate. Thesolvent was removed by distillation under the reduced pressure, and theresidue was purified by thin layer chromatography usingchloroform-methanol to give the title compound (54 mg, yield 56%).

¹H-NMR (CD₃OD, 400 MHz): δ 2.26-2.28 (m, 1H), 2.43 (s, 3H), 2.63 (s,3H), 3.79 (m, 2H), 3.81 (m, 2H), 4.01 (s, 3H), 4.25 (d, J=5.6 Hz, 2H),6.40 (d, J=5.4 Hz, 1H), 7.34 (s, 1H), 7.35-7.39 (m, 1H), 7.60 (s, 1H),7.60 (s, 1H), 8.24-8.26 (m, 1H), 8.32 (d, J=5.4 Hz, 1H), 8.40 (dd, J=1.7Hz, 4.9 Hz, 1H), 8.96 (d, J=2.2 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 462 (M+1)⁺

Compound 3517-Benzyloxy-6-methoxy-4-(2-methyl-quinolin-3-yloxy)-quinoline

3-Hydroxy-2-methyl-4-quinoline carboxylic acid (1.5 g),7-benzyloxy-4-chloro-6-methoxyquinoline (2 g), and4-(N,N-dimethylamino)-pyridine (2.4 g) were dissolved in1,2-dichlorobenzene (70 ml) to prepare a solution which was then stirredat 150° C. overnight. The reaction solution was cooled to roomtemperature, and the solvent was then removed by distillation under thereduced pressure. Water was added to the residue, and the mixture wasextracted with chloroform and was dried over anhydrous sodium sulfate.The solvent was removed by distillation under the reduced pressure. Theresidue was purified by column chromatography using hexane-acetone togive the title compound (2.4 g, yield 85%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.66 (s, 3H), 4.07 (s, 3H), 5.35 (s, 2H),6.37 (d, J=5.1 Hz, 1H), 7.29-7.37 (m, 1H), 7.37-7.44 (m, 2H), 7.49-7.57(m, 4H), 7.61 (s, 1H), 7.72 (ddd, J=1.5, 6.8, 8.3 Hz, 1H), 7.75 (d,J=8.1 Hz, 1H), 7.80 (s, 1H), 8.10 (d, J=8.6 Hz, 1H), 8.48 (d, J=5.1 Hz,1H)

Mass spectrometric value (ESI−MS, m/z): 423 (M+1)⁺

Compound 352 6-Methoxy-4-(2-methyl-quinolin-3-yloxy)-quinolin-7-ol

7-Benzyloxy-6-methoxy-4-(2-methyl-quinolin-3-yloxy)-quinoline (compound351) (1 g) was dissolved in N,N-dimethylformamide (15 ml) to prepare asolution. 20% Palladium hydroxide (100 mg) was added to the solution,and the mixture was stirred at room temperature under a hydrogen streamovernight. The reaction solution was filtered through Celite, and thesolvent was removed from the filtrate by distillation under the reducedpressure. The residue was purified by column chromatography usingchloroform-methanol to give the title compound (647 mg, yield 85%).

¹H-NMR (DMSO-d₆, 400 MHz): δ 2.54 (s, 3H), 3.93 (s, 3H), 6.43 (d, J=5.1Hz, 1H), 7.31 (s, 1H), 7.52-7.62 (m, 2H), 7.73 (dd, J=7.1, 7.1 Hz, 1H),7.92 (d, J=8.1 Hz, 1H), 8.00 (d, J=8.3 Hz, 1H), 8.13 (s, 1H), 8.40 (d,J=5.1 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 333 (M+1)⁺

Compound 3537-(2-Chloro-ethoxy)-6-methoxy-4-(2-methyl-quinolin-3-yloxy)-quinoline

6-Methoxy-4-(2-methyl-quinolin-3-yloxy)-quinolin-7-ol (compound 352)(200 mg) was dissolved in N,N-dimethylformamide (10 ml) to prepare asolution. 1-Bromo-2-chloroethane (432 mg) and potassium carbonate (416mg) were added to the solution, and the mixture was stirred at roomtemperature overnight. Water was added to the reaction solution, and themixture was extracted with chloroform. The chloroform layer was washedwith water and was then dried over anhydrous sodium sulfate. The solventwas removed by distillation under the reduced pressure, and the residuewas purified by thin layer chromatography using chloroform-methanol togive the title compound (186 mg, yield 78%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.66 (s, 3H), 3.98 (t, J=6.1 Hz, 2H), 4.06(s, 3H), 4.48 (t, J=6.1 Hz, 2H), 6.39 (d, J=5.1 Hz, 1H), 7.47 (s, 1H),7.52-7.58 (m, 1H), 7.62 (s, 1H), 7.72 (ddd, J=1.4, 7.1, 8.5 Hz, 1H),7.76 (d, J=8.0 Hz, 1H), 7.82 (s, 1H), 8.11 (d, J=8.0 Hz, 1H), 8.51 (d,J=5.1 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 395 (M+1)⁺

Compound 3542-[6-Methoxy-4-(2-methyl-quinolin-3-yloxy)-quinolin-7-yloxy]-ethylamine

2-{2-[6-Methoxy-4-(2-methyl-quinolin-3-yloxy)-quinolin-7-yloxy]-ethyl}-isoindole-1,3-dione(compound 367) (20 mg) was dissolved in N,N-dimethylformamide (2 ml) toprepare a solution, hydrazine (13 mg) was added to the solution, and themixture was stirred at room temperature for 4 hr. The solvent wasremoved by distillation under the reduced pressure, and the residue waspurified by thin layer chromatography using chloroform-methanol to givethe title compound (16 mg, yield 98%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.65 (s, 3H), 3.20-3.34 (m, 2H), 4.03 (s,3H), 4.23 (t, J=4.9 Hz, 2H), 6.37 (d, J=5.2 Hz, 1H), 7.46 (s, 1H), 7.53(dd, J=7.6, 7.6 Hz, 1H), 7.58 (s, 1H), 7.66-7.78 (m, 2H), 7.80 (s, 1H),8.09 (d, J=8.6 Hz, 1H), 8.48 (d, J=5.4 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 376 (M+1)⁺

Compound 355{2-[6-Methoxy-4-(2-methyl-quinolin-3-yloxy)-quinolin-7-yloxy]-ethyl}-dimethyl-amine

N,N-Dimethylformamide (2.5 ml) was added to7-(2-chloro-ethoxy)-6-methoxy-4-(2-methyl-quinolin-3-yloxy)-quinoline(compound 353) (100 mg), potassium carbonate (500 mg), sodium iodide (20mg), and water (0.05 ml), and the mixture was stirred at 80° C. for 3days. The solvent was removed by distillation under the reducedpressure, water was added to the residue, and the mixture was extractedwith chloroform. The chloroform layer was washed with water and was thendried over anhydrous sodium sulfate. The solvent was removed bydistillation under the reduced pressure, and the residue was purified bythin layer chromatography using chloroform-methanol to give the titlecompound (34.2 mg, yield 33%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.39 (s, 6H), 2.64 (s, 3H), 2.91 (t, J=5.6Hz, 2H), 4.01 (s, 3H), 4.31 (t, J=5.9 Hz, 2H), 6.35 (d, J=5.4 Hz, 1H),7.45 (s, 1H), 7.51 (dd, J=7.3, 7.3 Hz, 1H), 7.56 (s, 1H), 7.64-7.76 (m,2H), 7.79 (s, 1H), 8.08 (d, J=8.3 Hz, 1H), 8.47 (d, J=5.4 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 404 (M+1)⁺

Compound 356N-{2-[6-Methoxy-4-(2-methyl-quinolin-3-yloxy)-quinolin-7-yloxy]-ethyl}-guanidine

A solution of2-[6-methoxy-4-(2-methyl-quinolin-3-yloxy)-quinolin-7-yloxy]-ethylamine(compound 354) (340 mg) in dichloromethane (1 ml) andN,N-dimethylformamide (0.5 ml) were added to1,3-diboc-2-(trifluoromethylsulfonyl)guanidine (355 mg), and the mixturewas stirred at room temperature for 4 hr. The solvent was removed fromthe reaction solution under the reduced pressure, water was added to theresidue, and the mixture was extracted with chloroform. The chloroformlayer was washed with water and was then dried over anhydrous sodiumsulfate. The solvent was removed by distillation under the reducedpressure, and the residue was purified by thin layer chromatographyusing chloroform-methanol to giveN-{2-[6-methoxy-4-(2-methyl-quinolin-3-yloxy)-quinolin-7-yloxy]-ethyl}-N′,N″-diboc-guanidine(223 mg, yield 33%).

Trifluoroacetic acid (1 ml) was added toN-{2-[6-methoxy-4-(2-methyl-quinolin-3-yloxy)-quinolin-7-yloxy]-ethyl}-N′,N″-diboc-guanidine(222 mg) at 0° C., and the mixture was then stirred at 0° C. for 2 hr.The reaction solution was made alkaline by the addition of a 1 N aqueoussodium hydroxide solution and was extracted with n-butanol. Then-butanol layer was washed with water and was then dried over anhydrousmagnesium sulfate. The solvent was removed by distillation under thereduced pressure, and the residue was purified by thin layerchromatography using chloroform-methanol to give the title compound (150mg, yield 100%).

¹H-NMR (CD₃OD, 400 MHz): δ 2.62 (s, 3H), 3.75 (t, J=5.4 Hz, 2H), 4.08(s, 3H), 4.34 (t, J=5.4 Hz, 2H), 6.54 (d, J=5.2 Hz, 1H), 7.44 (s, 1H),7.62 (dd, J=7.6, 7.6 Hz, 1H), 7.72-7.82 (m, 2H), 7.91 (d, J=8.6 Hz, 1H),8.04 (d, J=8.3 Hz, 1H), 8.13 (s, 1H), 8.47 (d, J=5.4 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 418 (M+1)⁺

Compound 3574-{2-[6-Methoxy-4-(2-methyl-quinolin-3-yloxy)-quinolin-7-yloxy]-ethylcarbamoyl}-3,3-dimethyl-butanoicacid

N,N-Dimethylformamide (1 ml) was added to7-(2-chloro-ethoxy)-6-methoxy-4-(2-methyl-quinolin-3-yloxy)-quinoline(compound 353) (50 mg), potassium carbonate (53 mg), and4,4-dimethylpiperidine-2,6-dione (54 mg), and the mixture was stirred at80° C. overnight and then at 100° C. for one day. The reaction solutionwas cooled to room temperature, water was added to the reactionsolution, and the mixture was extracted with chloroform. The chloroformlayer was washed with water and was then dried over anhydrous sodiumsulfate. The solvent was removed by distillation under the reducedpressure, and the residue was purified by thin layer chromatographyusing chloroform-methanol to give the title compound (3.5 mg, yield 5%).

¹H-NMR (CDCl₃, 400 MHz): δ 1.13 (s, 6H), 2.36 (s, 2H), 2.46 (s, 2H),2.65 (s, 3H), 3.83-3.91 (m, 2H), 4.05 (s, 3H), 4.35 (t, J=4.9 Hz, 2H),6.40 (d, J=5.4 Hz, 1H), 6.80 (brs, 1H), 7.50-7.60 (m, 2H), 7.62 (s, 1H),7.68-7.82 (m, 2H), 7.83 (s, 1H), 8.11 (d, J=8.8 Hz, 1H), 8.49 (d, J=5.2Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 516 (M−1)⁻

Compound 3586-Methoxy-4-(2-methyl-quinolin-3-yloxy)-7-(2-piperidin-1-yl-ethoxy)-quinoline

N,N-Dimethylformamide (1 ml) was added to7-(2-chloro-ethoxy)-6-methoxy-4-(2-methyl-quinolin-3-yloxy)-quinoline(compound 353) (35 mg), potassium carbonate (37 mg), and piperidine (23mg), and the mixture was stirred at 75° C. overnight. The reactionsolution was cooled to room temperature, water was added to the reactionsolution, and the mixture was extracted with chloroform. The chloroformlayer was washed with water and was then dried over anhydrous magnesiumsulfate. The solvent was removed by distillation under the reducedpressure, and the residue was purified by thin layer chromatographyusing chloroform-methanol to give the title compound (35 mg, yield 89%).

¹H-NMR (CDCl₃, 400 MHz): δ 1.45 (m, 2H), 1.60-1.81 (m, 4H), 2.57-2.77(m, 7H), 2.95-3.10 (m, 2H), 4.04 (s, 3H), 4.41 (t, J=6.1 Hz, 2H), 6.38(d, J=5.4 Hz, 1H), 7.47 (s, 1H), 7.54 (dd, J=7.1, 7.1 Hz, 1H), 7.59 (s,1H), 7.68-7.79 (m, 2H), 7.81 (s, 1H), 8.10 (d, J=8.6 Hz, 1H), 8.50 (d,J=5.4 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 444 (M+1)⁺

Compound 359(1-{2-[6-Methoxy-4-(2-methyl-quinolin-3-yloxy)-quinolin-7-yloxy]-ethyl}-piperidin-3-yl)-methanol

N,N-Dimethylformamide (1 ml) was added to7-(2-chloro-ethoxy)-6-methoxy-4-(2-methyl-quinolin-3-yloxy)-quinoline(compound 353) (50 mg), potassium carbonate (53 mg), andpiperidin-3-yl-methanol (44 mg), and the mixture was stirred at 80° C.overnight. The reaction solution was then stirred at 100° C. for oneday, and the reaction solution was cooled to room temperature. Water wasadded thereto, and the mixture was extracted with chloroform. Thechloroform layer was washed with water and was then dried over anhydroussodium sulfate. The solvent was removed by distillation under thereduced pressure. The residue was purified by thin layer chromatographyusing chloroform-methanol to give the title compound (33 mg, yield 55%).

¹H-NMR (CDCl₃, 400 MHz): δ 1.12-1.20 (m, 1H), 1.58-1.85 (m, 3H),1.85-1.97 (m, 1H), 2.26-2.47 (m, 2H), 2.63-2.69 (m, 3H), 2.75-2.87 (m,1H), 2.89-3.03 (m, 3H), 3.60-3.66 (m, 2H), 4.01-4.08 (m, 3H), 4.34-4.46(m, 2H), 6.36-6.40 (m, 1H), 7.50-7.62 (m, 3H), 7.69-7.84 (m, 3H),8.08-8.13 (m, 1H), 8.46-8.52 (m, 1H)

Mass spectrometric value (ESI−MS, m/z): 474 (M+1)⁺

Compound 3601-{2-[6-Methoxy-4-(2-methyl-quinolin-3-yloxy)-quinolin-7-yloxy]-ethyl}-piperidine-3-carboxylicacid amide

N,N-Dimethylformamide (1 ml) was added to7-(2-chloro-ethoxy)-6-methoxy-4-(2-methyl-quinolin-3-yloxy)-quinoline(compound 353) (50 mg), potassium carbonate (53 mg), andpiperidine-3-carboxamide (49 mg), and the mixture was stirred at 80° C.overnight. The reaction solution was cooled to room temperature, waterwas added to the reaction solution, and the mixture was extracted withchloroform. The chloroform layer was washed with water and was thendried over anhydrous sodium sulfate. The solvent was removed bydistillation under the reduced pressure, and the residue was purified bythin layer chromatography using chloroform-methanol to give the titlecompound (45 mg, yield 72%).

¹H-NMR (CDCl₃, 400 MHz): δ 1.54-1.72 (m, 2H), 1.72-1.91 (m, 3H),1.91-2.04 (m, 1H), 2.24-2.37 (m, 1H), 2.41-2.60 (m, 2H), 2.60-2.68 (m,3H), 2.85-2.98 (m, 1H), 3.04-3.15 (m, 1H), 4.12-4.16 (m, 3H), 4.25-4.36(m, 2H), 5.32-5.48 (m, 1H), 6.32-6.41 (m, 1H), 7.41-7.49 (m, 1H),7.49-7.63 (m, 2H), 7.66-7.85 (m, 3H), 8.05-8.34 (m, 2H), 8.43-8.53 (m,1H)

Mass spectrometric value (ESI−MS, m/z): 487 (M+1)⁺

Compound 361 Ethyl1-{2-[6-methoxy-4-(2-methyl-quinolin-3-yloxy)-quinolin-7-yloxy]-ethyl}-piperidine-3-carboxylate

N,N-Dimethylformamide (1 ml) was added to7-(2-chloro-ethoxy)-6-methoxy-4-(2-methyl-quinolin-3-yloxy)-quinoline(compound 353) (50 mg), potassium carbonate (53 mg), and ethylpiperidine-3-carboxylate (60 mg), and the mixture was stirred at 80° C.overnight. The reaction solution was cooled to room temperature, waterwas added to the reaction solution, and the mixture was extracted withchloroform. The chloroform layer was washed with water and was thendried over anhydrous sodium sulfate, the solvent was removed bydistillation under the reduced pressure, and the residue was purified bythin layer chromatography using chloroform-methanol to give the titlecompound (36 mg, yield 54%).

¹H-NMR (CDCl₃, 400 MHz): δ 1.22-1.29 (m, 3H), 1.41-1.54 (m, 1H),1.58-1.71 (m, 1H), 1.71-1.82 (m, 1H), 1.92-2.04 (m, 1H), 2.15-2.27 (m,1H), 2.32-2.44 (m, 1H), 2.57-2.70 (m, 4H), 2.90-3.04 (m, 3H), 3.10-3.21(m, 1H), 4.00-4.07 (m, 3H), 4.07-4.19 (m, 2H), 4.31-4.39 (m, 2H),6.34-6.41 (m, 1H), 7.41-7.49 (m, 1H), 7.49-7.61 (m, 2H), 7.68-7.85 (m,3H), 8.07-8.14 (m, 1H), 8.46-8.54 (m, 1H)

Mass spectrometric value (ESI−MS, m/z): 538 (M+Na)⁺

Compound 3621-{2-[6-Methoxy-4-(2-methyl-quinolin-3-yloxy)-quinolin-7-yloxy]-ethyl}-piperidine4-carboxylic acid amide

N,N-Dimethylformamide (1 ml) was added to7-(2-chloro-ethoxy)-6-methoxy-4-(2-methyl-quinolin-3-yloxy)-quinoline(compound 353) (50 mg), potassium carbonate (53 mg), andpiperidine-4-carboxamide (49 mg), and the mixture was stirred at 80° C.overnight. The reaction solution was cooled to room temperature, waterwas added to the reaction solution, and the mixture was extracted withchloroform. The chloroform layer was washed with water and was thendried over anhydrous sodium sulfate. The solvent was removed bydistillation under the reduced pressure, and the residue was purified bythin layer chromatography using chloroform-methanol to give the titlecompound (20 mg, yield 32%).

¹H-NMR (CDCl₃, 400 MHz): δ 1.74-2.32 (m, 7H), 2.61-2.70 (m, 3H),2.92-3.04 (m, 2H), 3.06-3.19 (m, 2H), 3.97-4.10 (m, 3H), 4.29-4.41 (m,2H), 5.37-5.73 (m, 2H), 6.32-6.43 (m, 1H), 7.43-7.63 (m, 3H), 7.66-7.85(m, 3H), 8.07-8.15 (m, 1H), 8.45-8.55 (m, 1H)

Mass spectrometric value (ESI−MS, m/z): 487 (M+1)⁺

Compound 363 Ethyl1-{2-[6-methoxy-4-(2-methyl-quinolin-3-yloxy)-quinolin-7-yloxy]-ethyl}-piperidine-4-carboxylate

N,N-Dimethylformamide (1 ml) was added to7-(2-chloro-ethoxy)-6-methoxy-4-(2-methyl-quinolin-3-yloxy)-quinoline(compound 353) (50 mg), potassium carbonate (53 mg), and ethylpiperidine-4-carboxylate (60 mg), and the mixture was stirred at 80° C.overnight. The reaction solution was cooled to room temperature, waterwas added to the reaction solution, and the mixture was extracted withchloroform. The chloroform layer was washed with water and was thendried over anhydrous sodium sulfate. The solvent was removed bydistillation under the reduced pressure, and the residue was purified bythin layer chromatography using chloroform-methanol to give the titlecompound (48 mg, yield 73%).

¹H-NMR (CDCl₃, 400 MHz): δ 1.29-2.39 (m, 10H), 2.54-2.64 (m, 3H),2.90-3.10 (m, 4H), 4.01-4.41 (m, 7H), 6.33-6.43 (m, 1H), 7.42-7.66 (m,3H), 7.66-7.85 (m, 3H), 8.05-8.15 (m, 1H), 8.45-8.54 (m, 1H)

Mass spectrometric value (ESI−MS, m/z): 538 (M+Na)⁺

Compound 3641-{2-[6-Methoxy-4-(2-methyl-quinolin-3-yloxy)-quinolin-7-yloxy]-ethyl}-piperidin-4-ol

N,N-Dimethylformamide (1 ml) was added to7-(2-chloro-ethoxy)-6-methoxy-4-(2-methyl-quinolin-3-yloxy)-quinoline(compound 353) (50 mg), potassium carbonate (53 mg), and piperidin-4-ol(38 mg), and the mixture was stirred at 70° C. overnight. The reactionsolution was cooled to room temperature, water was added to the reactionsolution, and the mixture was extracted with chloroform. The chloroformlayer was washed with water and was then dried over anhydrous sodiumsulfate. The solvent was removed by distillation under the reducedpressure, and the residue was purified by thin layer chromatographyusing chloroform-methanol to give the title compound (24 mg, yield 41%).

¹H-NMR (CDCl₃, 400 MHz): δ 1.57-2.20 (m, 5H), 2.40-2.73 (m, 4H),2.93-3.18 (m, 4H), 3.71-3.93 (m, 1H), 3.99-4.09 (m, 3H), 4.34-4.51 (m,2H), 6.34-6.41 (m, 1H), 7.44-7.62 (m, 3H), 7.66-7.85 (m, 3H), 8.07-8.15(m, 1H), 8.46-8.55 (m, 1H)

Mass spectrometric value (ESI−MS, m/z): 460 (M+1)⁺

Compound 3656-Methoxy-4-(2-methyl-quinolin-3-yloxy)-7-(2-morpholin-4-yl-ethoxy)-quinoline

N,N-Dimethylformamide (1.5 ml) was added to7-(2-chloro-ethoxy)-6-methoxy-4-(2-methyl-quinolin-3-yloxy)-quinoline(compound 353) (50 mg), potassium carbonate (53 mg), and morpholine (33mg), and the mixture was stirred at 80° C. for 3 days. The reactionsolution was cooled to room temperature, water was added to the reactionsolution, and the mixture was extracted with chloroform. The chloroformlayer was washed with water and was then dried over anhydrous sodiumsulfate, the solvent was removed by distillation under the reducedpressure, and the residue was purified by thin layer chromatographyusing chloroform-methanol to give the title compound (23 mg, yield 41%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.66 (s, 3H), 3.40-3.74 (m, 8H), 4.05 (s,3H), 4.43-4.52 (m, 2H), 4.56-4.66 (m, 2H), 6.39 (d, J=5.1 Hz, 1H), 7.50(s, 1H), 7.55 (dd, J=7.6, 7.6 Hz, 1H), 7.61 (s, 1H), 7.69-7.79 (m, 2H),7.82 (s, 1H), 8.11 (d, J=8.3 Hz, 1H), 8.50 (d, J=5.1 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 446 (M+1)⁺

Compound 3666-Methoxy-4-(2-methyl-quinolin-3-yloxy)-7-(2-morpholin-4-yl-ethoxy)-quinolinehydrochloride

A hydrochloric acid/methanol solution (30 ml) was added to6-methoxy-4-(2-methyl-quinolin-3-yloxy)-7-(2-morpholin-4-yl-ethoxy)-quinoline(compound 365) (748 mg), and the mixture was stirred at room temperaturefor one hr. The solvent was removed by distillation under the reducedpressure to give the title compound (900 mg, yield 59%).

¹H-NMR (CD₃OD, 400 MHz): δ 2.97 (s, 3H), 3.44-3.53 (m, 2H), 3.67-4.01(m, 6H), 4.01-4.24 (m, 5H), 4.70-5.00 (m, 2H), 7.33 (d, J=5.6 Hz, 1H),7.76 (s, 1H), 7.97 (dd, J=7.8, 7.8 Hz, 1H), 8.03 (s, 1H), 8.18 (dd,J=7.3, 7.3 Hz, 1H), 8.24-8.37 (m, 2H), 8.85 (d, J=5.6 Hz, 1H), 9.12 (s,1H)

Mass spectrometric value (ESI−MS, m/z): 446 (M+1-3HCl)⁺

Compound 3672-{2-[6-Methoxy-4-(2-methyl-quinolin-3-yloxy)-quinolin-7-yloxy]-ethyl}-isoindole-1,3-dione

N,N-Dimethylformamide (3 ml) was added to6-methoxy-4-(2-methyl-quinolin-3-yloxy)-quinolin-7-ol (compound 352)(100 mg), 2-(2-bromo-ethyl)-isoindole-1,3-dione (229 mg) and potassiumcarbonate (125 mg), and the mixture was stirred at room temperatureovernight. The solvent was removed by distillation under the reducedpressure, water was added to the residue, and the mixture was extractedwith chloroform. The chloroform layer was washed with water and was thendried over anhydrous sodium sulfate. The solvent was removed bydistillation under the reduced pressure, and the residue was purified bythin layer chromatography using acetone-hexane to give the titlecompound (83 mg, yield 55%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.65 (s, 3H), 3.96 (s, 3H), 4.27 (t, J=5.9Hz, 2H), 4.49 (t, J=5.9 Hz, 2H), 6.39 (d, J=5.1 Hz, 1H), 7.48-7.57 (m,3H), 7.68-7.77 (m, 4H), 7.79 (s, 1H), 7.87-7.93 (m, 2H), 8.10 (d, J=8.6Hz, 1H), 8.49 (d, J=5.4 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 528 (M+Na)⁺

Compound 3687-(2-Imidazol-1-yl-ethoxy)-6-methoxy-4-(2-methyl-quinolin-3-yloxy)-quinoline

N,N-Dimethylformamide (1.5 ml) was added to7-(2-chloro-ethoxy)-6-methoxy-4-(2-methyl-quinolin-3-yloxy)-quinoline(compound 353) (50 mg), potassium carbonate (53 mg), and imidazole (26mg), and the mixture was stirred at 80° C. for 3 days. The reactionsolution was cooled to room temperature, water was added to the reactionsolution, and the mixture was extracted with chloroform. The chloroformlayer was washed with water and was then dried over anhydrous sodiumsulfate. The solvent was removed by distillation under the reducedpressure, and the residue was purified by thin layer chromatographyusing chloroform-methanol to give the title compound (31 mg, yield 57%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.65 (s, 3H), 4.06 (s, 3H), 4.41-4.54 (m,4H), 6.38 (d, J=5.1 Hz, 1H), 7.09 (s, 1H), 7.16 (s, 1H), 7.40 (s, 1H),7.55 (dd, J=7.6, 7.6 Hz, 1H), 7.61 (s, 1H), 7.68-7.80 (m, 3H), 7.81 (s,1H), 8.10 (d, J=8.3 Hz, 1H), 8.49 (d, J=5.1 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 427 (M+1)⁺

Compound 3692-[6-Methoxy-4-(2-methyl-quinolin-3-yloxy)-quinolin-7-yloxy]-ethanol

A solution of 2-bromo-ethanol (226 mg) in N,N-dimethylformamide (6 ml)was added to 6-methoxy-4-(2-methyl-quinolin-3-yloxy)-quinolin-7-ol(compound 352) (100 mg) and potassium carbonate (250 mg), and themixture was stirred at 70° C. overnight. The reaction solution wascooled to room temperature, water was added to the reaction solution,and the mixture was extracted with chloroform. The chloroform layer waswashed with water and was then dried over anhydrous sodium sulfate. Thesolvent was removed by distillation under the reduced pressure, and theresidue was purified by thin layer chromatography usingchloroform-acetone to give the title compound (51.3 mg, yield 45%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.66 (s, 3H), 4.05 (s, 3H), 4.11 (t, J=4.9Hz, 2H), 4.33 (t, J=4.9 Hz, 2H), 6.39 (d, J=5.1 Hz, 1H), 7.49 (s, 1H),7.55 (dd, J=7.1, 7.1 Hz, 1H), 7.61 (s, 1H), 7.67-7.79 (m, 2H), 7.82 (s,1H), 8.10 (d, J=8.3 Hz, 1H), 8.50 (d, J=5.1 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 377 (M+1)⁺

Compound 3702-[6-Methoxy-4-(2-methyl-quinolin-3-yloxy)-quinolin-7-yloxy]-acetamide

N,N-Dimethylformamide (1.5 ml) was added to6-methoxy-4-(2-methyl-quinolin-3-yloxy)-quinolin-7-ol (compound 352) (50mg), bromoacetamide (62 mg), and potassium carbonate (62 mg), and themixture was stirred at room temperature overnight. Water was added tothe reaction solution, and the mixture was extracted with ethyl acetate.The ethyl acetate layer was washed with water and was then dried overanhydrous sodium sulfate. The solvent was removed by distillation underthe reduced pressure, and the residue was purified by thin layerchromatography using chloroform-methanol to give the title compound (49mg, yield 83%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.65 (s, 3H), 4.09 (s, 3H), 4.76 (s, 2H),5.72 (bs, 1H), 6.48 (d, J=5.4 Hz, 1H), 6.85 (bs, 1H), 7.58 (dd, J=8.0,8.0 Hz, 1H), 7.68 (s, 1H), 7.72 (s, 1H), 7.73-7.81 (m, 2H), 7.87 (s,1H), 8.13 (d, J=8.5 Hz, 1H), 8.53 (d, J=5.4 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 412 (M+Na)⁺

Compound 371 Methyl[6-methoxy-4-(2-methyl-quinolin-3-yloxy)-quinolin-7-yloxy]-acetate

N,N-Dimethylformamide (1.5 ml) was added to6-methoxy-4-(2-methyl-quinolin-3-yloxy)-quinolin-7-ol (compound 352) (50mg), methyl boromoacetate (69 mg), and potassium carbonate (62 mg), andthe mixture was stirred at room temperature overnight. Water was addedto the reaction solution, and the mixture was extracted with ethylacetate. The ethyl acetate layer was washed with water and was thendried over anhydrous sodium sulfate. The solvent was removed bydistillation under the reduced pressure, and the residue was purified bythin layer chromatography using chloroform-methanol to give the titlecompound (23 mg, yield 38%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.64 (s, 3H), 3.82 (s, 3H), 4.06 (s, 3H),4.88 (s, 2H), 6.37 (d, J=5.2 Hz, 1H), 7.34 (s, 1H), 7.52 (dd, J=8.3, 8.3Hz, 1H), 7.62 (s, 1H), 7.69 (d, J=8.3, 8.3 Hz, 1H), 7.74 (d, i=8.0 Hz,1H), 7.80 (s, 1H), 8.08 (d, J=8.5 Hz, 1H), 8.47 (d, J=5.1 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 427 (M+Na)⁺

Compound 372 Ethyl[6-Methoxy-4-(2-methyl-quinolin-3-yloxy)-quinolin-7-yloxy]-acetate

N,N-Dimethylformamide (1.5 ml) was added to6-methoxy-4-(2-methyl-quinolin-3-yloxy)-quinolin-7-ol (compound 352) (50mg), ethyl bromoacetate (75 mg), and potassium carbonate (62 mg), andthe mixture was stirred at room temperature overnight. Water was addedto the reaction solution, and the mixture was extracted with ethylacetate. The ethyl acetate layer was washed with water and was thendried over anhydrous sodium sulfate. The solvent was removed bydistillation under the reduced pressure, and the residue was purified bythin layer chromatography using chloroform-methanol to give the titlecompound (31 mg, yield 49%).

¹H-NMR (CDCl₃, 400 MHz): δ 1.31 (t, J=7.1 Hz, 3H), 2.64 (s, 3H), 4.06(s, 3H), 4.29 (q, J=7.1 Hz, 2H), 4.87 (s, 2H), 6.38 (d, J=5.4 Hz, 1H),7.36 (s, 1H), 7.53 (dd, J=8.3, 8.3 Hz, 1H), 7.62 (s, 1H), 7.70 (d,J=8.3, 8.3 Hz, 1H), 7.74 (d, J=8.1 Hz, 1H), 7.80 (s, 1H), 8.09 (d, J=8.3Hz, 1H), 8.48 (d, J=5.1 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 441 (M+Na)⁺

Compound 373 Diethyl2-[6-methoxy-4-(2-methyl-quinolin-3-yloxy)-quinolin-7-yloxy]-malonate

N,N-Dimethylformamide (3 ml) was added to6-methoxy-4-(2-methyl-quinolin-3-yloxy)-quinolin-7-ol (compound 352) (50mg), diethyl 2-bromo-malonate (75 mg), and potassium carbonate (62 mg),and the mixture was stirred at room temperature overnight. Water wasadded to the reaction solution, and the mixture was extracted with ethylacetate. The ethyl acetate layer was washed with water and was thendried over anhydrous sodium sulfate. The solvent was removed bydistillation under the reduced pressure, and the residue was purified bythin layer chromatography using hexane-acetone to give the titlecompound (134 mg, yield 88%).

¹H-NMR (CDCl₃, 400 MHz): δ 1.33 (t, J=7.1 Hz, 6H), 2.64 (s, 3H), 4.05(s, 3H), 4.28-4.42 (m, 4H), 5.35 (s, 1H), 6.37 (d, J=5.1 Hz, 1H), 7.43(s, 1H), 7.53 (dd, J=7.6, 7.6 Hz, 1H), 7.62 (s, 1H), 7.70 (d, J=8.3, 8.3Hz, 1H), 7.74 (d, J=8.1 Hz, 1H), 7.80 (s, 1H), 8.09 (d, J=8.3 Hz, 1H),8.48 (d, J=5.1 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 491 (M+1)⁺

Compound 3742-[6-Methoxy-4-(2-methyl-quinolin-3-yloxy)-quinolin-7-yloxy]-propane-1,3-diol

Diethyl2-[6-methoxy-4-(2-methyl-quinolin-3-yloxy)-quinolin-7-yloxy]-malonate(compound 373) (50 mg) was dissolved in tetrahydrofuran (1 ml) toprepare a solution. Lithium aluminum hydride (10 mg) was added to thesolution at 0° C., and the mixture was stirred at 0° C. for 3 hr andthen at room temperature for 2 hr. Water was added to the reactionsolution to stop the reaction. The mixture was filtered through Celite,water was then added to the filtrate, and the mixture was extracted withchloroform. The chloroform layer was washed with water and was thendried over anhydrous sodium sulfate. The solvent was removed bydistillation under the reduced pressure, and the residue was purified bythin layer chromatography using chloroform-methanol to give the titlecompound (9.1 mg, yield 22%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.64 (s, 3H), 4.02 (s, 3H), 4.03-4.10 (m,4H), 4.65-4.71 (m, 1H), 6.37 (d, J=5.1 Hz, 1H), 7.55 (dd, J=7.6, 7.6 Hz,1H), 7.61 (s, 1H), 7.67-7.79 (m, 3H), 7.82 (s, 1H), 8.10 (d, J=8.3 Hz,1H), 8.47 (d, J=5.4 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 407 (M+1)⁺

Compound 3757-(3-Chloro-propoxy)-6-methoxy-4-(2-methyl-quinolin-3-yloxy)-quinoline

6-Methoxy-4-(2-methyl-quinolin-3-yloxy)-quinolin-7-ol (compound 352)(200 mg) was dissolved in N,N-dimethylformamide (10 ml) to prepare asolution. 1-Bromo-3-chloropropane (474 mg) and potassium carbonate (416mg) were added to the solution, and the mixture was stirred at roomtemperature overnight. Water was added to the reaction solution, and themixture was extracted with chloroform. The chloroform layer was washedwith water and was then dried over anhydrous sodium sulfate. The solventwas removed by distillation under the reduced pressure, and the residuewas purified by thin layer chromatography using chloroform-methanol togive the title compound (203 mg, yield 83%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.36-2.46 (m, 2H), 2.66 (s, 3H), 3.83 (t,J=6.4 Hz, 2H), 4.04 (s, 3H), 4.38 (t, J=6.1 Hz, 2H), 6.38 (d, J=5.1 Hz,1H), 7.49 (s, 1H), 7.52-7.58 (m, 1H), 7.59 (s, 1H), 7.72 (ddd, J=1.5,7.1, 8.6 Hz, 1H), 7.76 (d, J=8.1 Hz, 1H), 7.81 (s, 1H), 8.11 (d, J=8.5Hz, 1H), 8.50 (d, J=5.4 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 409 (M+1)⁺

Compound 3763-[6-Methoxy-4-(2-methyl-quinolin-3-yloxy)-quinolin-7-yloxy]-propylamine

2-{3-[6-Methoxy-4-(2-methyl-quinolin-3-yloxy)-quinolin-7-yloxy]-propyl}-isoindole-1,3-dione(compound 380) (21 mg) was dissolved in N,N-dimethylformamide (2 ml) toprepare a solution. Hydrazine (13 mg) was added to the solution, and themixture was stirred at room temperature for 4 hr. The solvent wasremoved by distillation under the reduced pressure. The residue waspurified by thin layer chromatography using chloroform-methanol to givethe title compound (15 mg, yield 100%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.03-2.16 (m, 2H), 2.65 (s, 3H), 2.98 (t,J=6.6 Hz, 2H), 4.03 (s, 3H), 4.31 (t, J=6.6 Hz, 2H), 6.36 (d, J=5.4 Hz,1H), 7.46 (s, 1H), 7.53 (dd, J=8.0, 8.0 Hz, 1H), 7.57 (s, 1H), 7.66-7.78(m, 2H), 7.80 (s, 1H), 8.09 (d, J=8.5 Hz, 1H), 8.48 (d, J=5.4 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 390 (M+1)⁺

Compound 377N-{3-[6-Methoxy-4-(2-methyl-quinolin-3-yloxy)-quinolin-7-yloxy]-propyl}-guanidine

N,N-Dimethylformamide (1 ml) was added to7-(3-chloro-propoxy)-6-methoxy-4-(2-methyl-quinolin-3-yloxy)-quinoline(compound 375) (40 mg), potassium carbonate (41 mg), and guanidinehydrochloride (28 mg). Sodium hydride (39 mg) was added to the mixture,and the mixture was stirred at room temperature overnight. Water wasadded to the reaction solution, and the mixture was extracted withn-butanol. The n-butanol layer was washed with water and was then driedover anhydrous magnesium sulfate. The solvent was removed bydistillation under the reduced pressure, and the residue was purified bythin layer chromatography using chloroform-methanol to give the titlecompound (7 mg, yield 17%).

¹H-NMR (CD₃OD, 400 MHz): δ 2.17-2.30 (m, 2H), 2.63 (s, 3H), 3.50 (t,J=6.8 Hz, 2H), 4.05 (s, 3H), 4.31 (t, J=5.9 Hz, 2H), 6.53 (dd, J=2.2,5.4 Hz, 1H), 7.42 (d, J=3.2 Hz, 1H), 7.61 (dd, J=7.1, 7.1 Hz, 1H), 7.73(d, J=3.4 Hz, 1H), 7.78 (dd, J=7.3, 7.3 Hz, 1H), 7.92 (d, J=8.3 Hz, 1H),8.05 (d, J=8.5 Hz, 1H), 8.13 (s, 1H), 8.46 (d, J=5.1 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 432 (M+1)⁺

Compound 3786-Methoxy-4-(2-methyl-quinolin-3-yloxy)-7-(3-piperidin-1-yl-propoxy)-quinoline

N,N-Dimethylformamide (1 ml) was added to7-(3-chloro-propoxy)-6-methoxy-4-(2-methyl-quinolin-3-yloxy)-quinoline(compound 375) (40 mg), potassium carbonate (41 mg), and piperidine (25mg), and the mixture was stirred at 75° C. overnight. The reactionsolution was cooled to room temperature, water was added to the reactionsolution, and the mixture was extracted with chloroform. The chloroformlayer was washed with water and was then dried over anhydrous magnesiumsulfate. The solvent was removed by distillation under the reducedpressure, and the residue was purified by thin layer chromatographyusing chloroform-methanol to give the title compound (32 mg, yield 72%).

¹H-NMR (CDCl₃, 400 MHz): δ 1.43-2.22 (m, 6H), 2.32-2.50 (m, 2H),2.60-3.10 (m, 9H), 4.03 (s, 3H), 4.29 (t, J=6.1 Hz, 2H), 6.38 (d, J=5.4Hz, 1H), 7.45 (s, 1H), 7.52-7.58 (m, 1H), 7.58 (s, 1H), 7.72 (ddd,J=1.4, 6.8, 8.3 Hz, 1H), 7.76 (d, J=8.0 Hz, 1H), 7.81 (s, 1H), 8.10 (d,J=7.8 Hz, 1H), 8.50 (d, J=5.4 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 458 (M+1)⁺

Compound 3796-Methoxy-4-(2-methyl-quinolin-3-yloxy)-7-(3-morpholin-4-yl-propoxy)-quinoline

N,N-Dimethylformamide (1.5 ml) was added to7-(3-chloro-propoxy)-6-methoxy-4-(2-methyl-quinolin-3-yloxy)-quinoline(compound 375) (52 mg), potassium carbonate (53 mg), and morpholine (33mg), and the mixture was stirred at 80° C. for 3 days. The reactionsolution was cooled to room temperature, water was added to the reactionsolution, and the mixture was extracted with chloroform. The chloroformlayer was washed with water and was then dried over anhydrous sodiumsulfate. The solvent was removed by distillation under the reducedpressure, and the residue was purified by thin layer chromatographyusing chloroform-methanol to give the title compound (31 mg, yield 53%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.11-2.20 (m, 2H), 2.41-2.55 (m, 4H), 2.60(t, J=7.1 Hz, 2H), 2.66 (s, 3H), 3.71-3.77 (m, 4H), 4.05 (s, 3H), 4.30(t, J=6.6 Hz, 2H), 6.38 (d, J=5.4 Hz, 1H), 7.48 (s, 1H), 7.52-7.58 (m,1H), 7.58 (s, 1H), 7.72 (ddd, J=1.5, 7.1, 8.6 Hz, 1H), 7.75 (d, J=8.0Hz, 1H), 7.81 (s, 1H), 8.10 (d, J=8.6 Hz, 1H), 8.50 (d, J=5.4 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 460 (M+1)⁺

Compound 3802-{3-[6-Methoxy-4-(2-methyl-quinolin-3-yloxy)-quinolin-7-yloxy]-propyl}-isoindole-1,3-dione

N,N-Dimethylformamide (3 ml) was added to6-methoxy-4-(2-methyl-quinolin-3-yloxy)-quinolin-7-ol (compound 352)(100 mg), 2-(3-bromo-propyl)-isoindole-1,3-dione (242 mg), and potassiumcarbonate (125 mg), and the mixture was stirred at room temperatureovernight. The solvent was removed by distillation under the reducedpressure, water was added to the residue, and the mixture was extractedwith chloroform. The chloroform layer was washed with water and was thendried over anhydrous sodium sulfate. The solvent was removed bydistillation under the reduced pressure, and the residue was purified bythin layer chromatography using acetone-hexane to give the titlecompound (108 mg, yield 69%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.29-2.43 (m, 2H), 2.66 (s, 3H), 3.80 (s,3H), 3.99 (t, J=6.6 Hz, 2H), 4.29 (t, J=6.1 Hz, 2H), 6.37 (d, J=5.4 Hz,1H), 7.41 (s, 1H), 7.49 (s, 1H), 7.52 (dd, J=7.1, 7.1 Hz, 1H), 7.65-7.78(m, 4H), 7.79 (s, 1H), 7.81-7.88 (m, 2H), 8.10 (d, J=8.6 Hz, 1H), 8.48(d, J=5.2 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 542 (M+Na)⁺

Compound 3817-(3-Imidazol-1-yl-propoxy)-6-methoxy-4-(2-methyl-quinolin-3-yloxy)-quinoline

N,N-Dimethylformamide (1.5 ml) was added to7-(3-chloro-propoxy)-6-methoxy-4-(2-methyl-quinolin-3-yloxy)-quinoline(compound 375) (52 mg), potassium carbonate (53 mg), and imidazole (26mg), and the mixture was stirred at 80° C. for 3 days. The reactionsolution was cooled to room temperature, water was added to the reactionsolution, and the mixture was extracted with chloroform. The chloroformlayer was washed with water and was then dried over anhydrous sodiumsulfate. The solvent was removed by distillation under the reducedpressure, and the residue was purified by thin layer chromatographyusing chloroform-methanol to give the title compound (31 mg, yield 81%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.36-2.43 (m, 2H), 2.67 (s, 3H), 4.07 (s,3H), 4.17 (t, J=5.0 Hz, 2H), 4.29 (t, J=6.8 Hz, 2H), 6.39 (d, J=5.4 Hz,1H), 6.97 (s, 1H), 7.07 (s, 1H), 7.41 (s, 1H), 7.53 (s, 1H), 7.59 (dd,J=8.3, 8.3 Hz, 1H), 7.62 (s, 1H), 7.69-7.77 (m, 1H), 7.76 (d, J=8.1 Hz,1H), 7.82 (s, 1H), 8.11 (d, J=8.5 Hz, 1H), 8.50 (d, J=5.4 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 463 (M+Na)⁺

Compound 3823-[6-Methoxy-4-(2-methyl-quinolin-3-yloxy)-quinolin-7-yloxy]-propan-1-ol

N,N-Dimethylformamide (2 ml) was added to7-(3-chloro-propoxy)-6-methoxy-4-(2-methyl-quinolin-3-yloxy)-quinoline(compound 375) (69 mg), potassium carbonate (70 mg), and water (10 mg),and the mixture was stirred at 80° C. for 3 days. The reaction solutionwas cooled to room temperature, water was added to the reactionsolution, and the mixture was extracted with chloroform. The chloroformlayer was washed with water and was then dried over anhydrous sodiumsulfate. The solvent was removed by distillation under the reducedpressure, and the residue was purified by thin layer chromatographyusing chloroform-methanol to give the title compound (40 mg, yield 61%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.15-2.25 (m, 2H), 2.65 (s, 3H), 2.95 (t,J=5.4 Hz, 2H), 4.04 (s, 3H), 4.41 (t, J=6.1 Hz, 2H), 6.38 (d, J=5.4 Hz,1H), 7.51 (s, 1H), 7.54 (dd, J=7.3, 7.3 Hz, 1H), 7.58 (s, 1H), 7.68-7.78(m, 2H), 7.82 (s, 1H), 8.10 (d, J=8.5 Hz, 1H), 8.49 (d, J=5.1 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 391 (M+1)⁺

Compound 3836-Methoxy-4-(2-methyl-quinolin-3-yloxy)-7-oxiranylmethoxy-quinoline

N,N-Dimethylformamide (3 ml) was added to6-methoxy-4-(2-methyl-quinolin-3-yloxy)-quinolin-7-ol (compound 352)(100 mg), potassium carbonate (125 mg), and epibromohydrin (124 mg), andthe mixture was stirred at 80° C. overnight. The reaction solution wascooled to room temperature, water was added to the reaction solution,and the mixture was extracted with chloroform. The chloroform layer waswashed with water and was then dried over anhydrous sodium sulfate. Thesolvent was removed by distillation under the reduced pressure, and theresidue was purified by thin layer chromatography usingchloroform-methanol to give the title compound (62 mg, yield 53%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.66 (s, 3H), 2.83-2.89 (m, 1H), 2.94-3.01(m, 1H), 3.49-3.57 (m, 1H), 4.06 (s, 3H), 4.21 (dd, J=5.6, 11.2 Hz, 1H),4.46 (dd, J=3.4, 11.5 Hz, 1H), 6.38 (d, J=5.4 Hz, 1H), 7.48 (s, 1H),7.55 (dd, J=7.8, 7.8 Hz, 1H), 7.60 (s, 1H), 7.69-7.80 (m, 2H), 7.82 (s,1H), 8.10 (d, J=8.6 Hz, 1H), 8.50 (d, J=5.2 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 389 (M+1)⁺

Compound 3843-[6-Methoxy-4-(2-methyl-quinolin-3-yloxy)-quinolin-7-yloxy]-propane-1,2-diol

6-Methoxy-4-(2-methyl-quinolin-3-yloxy)-7-oxiranylmethoxy-quinoline(compound 383) (30 mg) was dissolved in dichloromethane (1.5 ml) toprepare a solution. Trifluoroacetic acid (1 ml) was added to thesolution at 0° C., and the mixture was then stirred at 0° C. for 2 hr.The reaction solution was made alkaline by the addition of a 1 N aqueoussodium hydroxide solution, and the mixture was extracted withchloroform. The chloroform layer was washed with water and was thendried over anhydrous sodium sulfate. The solvent was removed bydistillation under the reduced pressure, and the residue was purified bythin layer chromatography using chloroform-methanol to give the titlecompound (21 mg, yield 67%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.65 (s, 3H), 3.86-3.97 (m, 2H), 4.04 (s,3H), 4.22-4.35 (m, 2H), 4.39 (dd, J=3.9, 9.8 Hz, 1H), 6.41 (d, J=5.4 Hz,1H), 7.55 (dd, J=7.6, 7.6 Hz, 1H), 7.57 (s, 1H), 7.60 (s, 1H), 7.72 (d,J=7.1 Hz, 1H), 7.76 (d, J=8.5 Hz, 1H), 7.83 (s, 1H), 8.11 (d, J=8.6 Hz,1H), 8.50 (d, J=5.4 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 407 (M+1)⁺

Compound 385(S)-3-[6-Methoxy-4-(2-methyl-quinolin-3-yloxy)-quinolin-7-yloxy]-propane-1,2-diol

N,N-Dimethylformamide (2 ml) was added to6-methoxy-4-(2-methyl-quinolin-3-yloxy)-quinolin-7-ol (compound 352) (50mg), potassium carbonate (62 mg), and (S)-epichlorohydrin (42 mg), andthe mixture was stirred at 90° C. overnight. The reaction solution wascooled to room temperature, water was added to the reaction solution,and the mixture was extracted with ethyl acetate. The ethyl acetatelayer was washed with water and was then dried over anhydrous sodiumsulfate. The solvent was removed by distillation under the reducedpressure, and the residue was purified by thin layer chromatographyusing hexane-acetone to give(S)-6-methoxy-4-(2-methyl-quinolin-3-yloxy)-7-oxiranylmethoxy-quinoline(33 mg, yield 54%).

(S)-6-Methoxy-4-(2-methyl-quinolin-3-yloxy)-7-oxiranylmethoxy-quinoline(30 mg) was dissolved in dichloromethane (1 ml) to prepare a solution.Trifluoroacetic acid (1 ml) was added dropwise to the solution at 0° C.The mixture was then stirred at room temperature for 3 hr. The reactionsolution was made alkaline by the addition of a saturated aqueous sodiumhydrogencarbonate solution and was extracted with ethyl acetate. Theethyl acetate layer was washed with water and was then dried overanhydrous sodium sulfate. The solvent was removed by distillation underthe reduced pressure, and the residue was purified by thin layerchromatography using chloroform-methanol to give the title compound (24mg, yield 76%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.65 (s, 3H), 3.86-3.97 (m, 2H), 4.04 (s,3H), 4.22-4.35 (m, 2H), 4.39 (dd, J=3.9, 9.8 Hz, 1H), 6.41 (d, J=5.4 Hz,1H), 7.55 (dd, J=7.6, 7.6 Hz, 1H), 7.57 (s, 1H), 7.60 (s, 1H), 7.72 (d,J=7.1 Hz, 1H), 7.76 (d, J=8.5 Hz, 1H), 7.83 (s, 1H), 8.11 (d, J=8.6 Hz,1H), 8.50 (d, J=5.4 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 407 (M+1)⁺

Compound 386(R)-3-[6-Methoxy-4-(2-methyl-quinolin-3-yloxy)-quinolin-7-yloxy]-propane-1,2-diol

N,N-Dimethylformamide (3 ml) was added to6-methoxy-4-(2-methyl-quinolin-3-yloxy)-quinolin-7-ol (compound 352)(100 mg), potassium carbonate (125 mg), and (R)-epichlorohydrin (124mg), and the mixture was stirred at 70° C. overnight. The reactionsolution was cooled to room temperature, water was added to the reactionsolution, and the mixture was extracted with ethyl acetate. The ethylacetate layer was washed with water and was then dried over anhydroussodium sulfate, and the solvent was removed by distillation under thereduced pressure. The residue was dissolved in dichloromethane (3 ml),trifluoroacetic acid (3 ml) was added dropwise to the solution at 0° C.,and the mixture was then stirred at room temperature for 3 hr. Thereaction solution was made alkaline by the addition of a 1 N aqueoussodium hydroxide solution, and the mixture was extracted withchloroform. The chloroform layer was washed with water and was thendried over anhydrous sodium sulfate. The solvent was removed bydistillation under the reduced pressure, and the residue was purified bythin layer chromatography using chloroform-methanol to give the titlecompound (24 mg, yield 76%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.65 (s, 3H), 3.86-3.97 (m, 2H), 4.04 (s,3H), 4.22-4.35 (m, 2H), 4.39 (dd, J=3.9, 9.8 Hz, 1H), 6.41 (d, J=5.4 Hz,1H), 7.55 (dd, J=7.6, 7.6 Hz, 1H), 7.57 (s, 1H), 7.60 (s, 1H), 7.72 (d,J=7.1 Hz, 1H), 7.76 (d, J=8.5 Hz, 1H), 7.83 (s, 1H), 8.11 (d, J=8.6 Hz,1H), 8.50 (d, J=5.4 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 407 (M+1)⁺

Compound 3872-[6-Methoxy-4-(2-methyl-quinolin-3-yloxy)-quinolin-7-yloxymethyl]-propane-1,3-diol

6-Methoxy-4-(2-methyl-quinolin-3-yloxy)-quinolin-7-ol (compound 352) (50mg) and triphenylphosphine (158 mg) were dissolved in tetrahydrofuran (1ml) to prepare a solution. A solution of diethylazocarbodiimide (105 mg)in (2,2-dimethyl[1,3]dioxan-5-yl)-methanol (27 mg) and tetrahydrofuran(0.2 ml) was added to the solution, and the mixture was stirred at roomtemperature for 5 hr. A 1 N aqueous sulfuric acid solution (1 ml) wasthen added to the reaction solution, and the mixture was stirred at roomtemperature overnight. The reaction solution was made alkaline by theaddition of 1 N sodium hydroxide, and the mixture was extracted withethyl acetate. The ethyl acetate layer was washed with water and wasdried over anhydrous sodium sulfate. The solvent was removed bydistillation under the reduced pressure, and the residue was purified bythin layer chromatography using chloroform-methanol to give the titlecompound (29 mg, yield 45%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.34-2.46 (m, 1H), 2.65 (s, 3H), 3.95-4.05(m, 4H), 4.05 (s, 3H), 4.46 (d, J=5.6 Hz, 2H), 6.44 (dd, J=2.2, 5.6 Hz,1H), 7.57 (dd, J=7.1, 7.1 Hz, 1H), 7.61 (s, 1H), 7.67-7.81 (m, 3H), 7.86(s, 1H), 8.11 (d, J=8.5 Hz, 1H), 8.49 (d, J=5.6 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 443 (M+Na)⁺

Compound 3882,2-Bis-hydroxymethyl-3-[6-methoxy-4-(2-methyl-quinolin-3-yloxy)-quinolin-7-yloxy]-propan-1-ol

N,N-Dimethylformamide (1.5 ml) was added to6-methoxy-4-(2-methyl-quinolin-3-yloxy)-quinolin-7-ol (compound 352) (50mg), potassium carbonate (62 mg), and2-bromomethyl-2-hydroxymethyl-propane-1,3-diol (90 mg), and the mixturewas stirred at 80° C. overnight. The reaction solution was cooled toroom temperature, water was added to the reaction solution, and themixture was extracted with ethyl acetate. The ethyl acetate layer waswashed with water and was then dried over anhydrous sodium sulfate. Thesolvent was removed by distillation under the reduced pressure, and theresidue was dissolved in dichloromethane (3 ml) to prepare a solution.Trifluoroacetic acid (3 ml) was added dropwise to the solution at 0° C.,and the mixture was then stirred at room temperature for 3 hr. Thereaction solution was made alkaline by the addition of a 1 N aqueoussodium hydroxide solution and was extracted with chloroform. Thechloroform layer was washed with water and was then dried over anhydroussodium sulfate. The solvent was removed by distillation under thereduced pressure, and the residue was purified by thin layerchromatography using chloroform-methanol to give the title compound (14mg, yield 21%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.64 (s, 3H), 3.91 (s, 6H), 4.00 (s, 3H),4.35 (s, 2H), 6.37 (d, J=5.1 Hz, 1H), 7.50 (s, 1H), 7.51-7.59 (m, 2H),7.68-7.80 (m, 2H), 7.82 (s, 1H), 8.10 (d, J=8.3 Hz, 1H), 8.47 (d, J=5.1Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 473 (M+Na)⁺

Compound 3892-Bromomethyl-2-[6-methoxy-4-(2-methyl-quinolin-3-yloxy)-quinolin-7-yloxymethyl]-propane-1,3-diol

N,N-Dimethylformamide (9 ml) was added to6-methoxy-4-(2-methyl-quinolin-3-yloxy)-quinolin-7-ol (compound 352)(300 mg), potassium carbonate (375 mg), and2-bis-(bromomethyl)-propane-1,3-diol (710 mg), and the mixture wasstirred at 45° C. for 3 days. The reaction solution was cooled to roomtemperature, and the solvent was removed by distillation under thereduced pressure. Water was added to the residue, and the mixture wasextracted with ethyl acetate. The ethyl acetate layer was washed withwater and was then dried over anhydrous sodium sulfate. The solvent wasremoved by distillation under the reduced pressure, and the residue waspurified by thin layer chromatography using chloroform-methanol to givethe title compound (132 mg, yield 28%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.58 (s, 3H), 3.70 (s, 3H), 4.08 (s, 2H),4.47 (s, 2H), 4.57 (d, J=6.6 Hz, 2H), 4.59 (d, J=6.4 Hz, 2H), 6.32 (d,J=5.4 Hz, 1H), 7.43 (s, 1H), 7.45-7.51 (m, 1H), 7.51 (s, 1H), 7.63-7.72(m, 2H), 7.76 (s, 1H), 8.03 (d, J=8.3 Hz, 1H), 8.42 (d, J=5.4 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 535 (M+Na)⁺

Compound 3901-[3-(7-Hydroxy-6-methoxy-quinolin-4-yloxy)-quinolin-2-yl]-ethanone

3-Hydroxy-quinoline-2-carbaldehyde (1.7 g) was dissolved intetrahydrofuran (50 ml) to prepare a solution which was then cooled to−78° C. Methylmagnesium bromide (32 ml) was gradually added dropwise tothe solution, and the mixture was stirred at room temperature overnight.Water was added to the reaction solution, and the mixture wasneutralized with 100% hydrochloric acid and was extracted withchloroform. The chloroform layer was washed with saturated brine and wasdried over anhydrous sodium sulfate. The solvent was removed bydistillation under the reduced pressure, and the residue was used in thenext reaction without purification.

The residue (1.73 g) was dissolved in methanol (8 ml) anddichloromethane (24 ml) to prepare a solution. Manganese dioxide (19.5g) was added to the solution, and the mixture was stirred at roomtemperature for 2 days. The reaction solution was filtered throughCelite and was then washed with chloroform and methanol. The solvent wasremoved by distillation under the reduced pressure, and the residue waspurified by column chromatography using hexane-acetone to give(3-hydroxy-quinolin-2-yl)-ethanone (878 mg, yield 54%).

(3-Hydroxy-quinolin-2-yl)-ethanone (878 mg),7-benzyloxy-4-chloro-6-methoxyquinoline (7.03 g), and4-dimethylaminopyridine (3.44 g) were suspended in o-dichlorobenzene (20ml), and the mixture was stirred at 130° C. overnight. The reactionsolution was cooled to room temperature, water was then added thereto,and the mixture was extracted with chloroform. The chloroform layer waswashed with saturated brine and was dried over anhydrous sodium sulfate.The solvent was removed by distillation under the reduced pressure, andthe residue was purified by column chromatography usingchloroform-acetone to give1-[3-(7-benzyloxy-6-methoxy-quinolin-4-yloxy)-quinolin-2-yl]-ethanone(758 mg, yield 36%).

1-[3-(7-Benzyloxy-6-methoxy-quinolin-4-yloxy)-quinolin-2-yl]-ethanone(758 mg) was dissolved in trifluoroacetic acid (6 ml) to prepare asolution, methanesulfonic acid (0.6 ml) was added to the solution, andthe mixture was stirred at 70° C. for 1.5 hr. The reaction solution wascooled to room temperature, and the solvent was removed by distillationunder the reduced pressure. An aqueous sodium hydrogencarbonate solutionwas then added to the residue, and the mixture was extracted withchloroform. The chloroform layer was washed with saturated brine and wasdried over anhydrous sodium sulfate, the solvent was removed bydistillation under the reduced pressure, and the residue was purified bycolumn chromatography using chloroform-methanol to give the titlecompound (609 mg, yield 100%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.77 (s, 3H), 4.10 (s, 3H), 6.36 (d, J=5.4Hz, 1H), 7.63 (s, 1H), 7.67 (s, 1H), 7.68-7.72 (m, 1H), 7.79-7.85 (m,2H), 7.98 (s, 1H), 8.24 (d, J=8.5 Hz, 1H), 8.49 (d, J=5.4 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 361 (M+1)⁺

Compound 3911-{3-[6-Methoxy-7-(2-morpholin-4-yl-ethoxy)-quinolin-4-yloxy]-quinolin-2-yl}-ethanone

1-[3-(7-Hydroxy-6-methoxy-quinolin-4-yloxy)-quinolin-2-yl]-ethanone(compound 390) (86 mg) was dissolved in N,N-dimethylformamide (2 ml) toprepare a solution. Potassium carbonate (330 mg) and1-bromo-2-chloroethane (1 ml) were added to the solution, and themixture was stirred at room temperature overnight. Water was added tothe reaction solution, and the mixture was extracted with ethyl acetate.The ethyl acetate layer was then washed with saturated brine and wasdried over anhydrous sodium sulfate. The solvent was removed bydistillation under the reduced pressure, and the residue was purified bythin layer chromatography using acetone-chloroform to give1-{3-[7-(2-chloro-ethoxy)-6-methoxy-quinolin-4-yloxy]-quinolin-2-yl}-ethanone(75 mg, yield 74%).

1-{3-[7-(2-Chloro-ethoxy)-6-methoxy-quinolin-4-yloxy]-quinolin-2-yl}-ethanone(37 mg) was dissolved in N,N-dimethylformamide (1 ml) to prepare asolution. Potassium carbonate (242 mg) and morpholine (0.1 ml) wereadded to the solution, and the mixture was stirred at 60° C. for 2 days.Water was added to the reaction solution and was extracted with ethylacetate. The ethyl acetate layer was then washed with saturated brineand was dried over anhydrous sodium sulfate. The solvent was removed bydistillation under the reduced pressure, and the residue was purified bythin layer chromatography using chloroform-methanol to give the titlecompound (11 mg, yield 27%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.69 (s, 4H), 2.77 (s, 3H), 2.97-3.02 (m,2H), 3.77-3.79 (m, 4H), 4.04 (s, 3H), 4.37-4.40 (m, 2H), 6.37 (d, J=5.4Hz, 1H), 7.51 (s, 1H), 7.63 (s, 1H), 7.68-7.71 (m, 1H), 7.80-7.84 (m,2H), 7.97 (s, 1H), 8.24 (d, J=8.5 Hz, 1H), 8.47 (d, J=5.4 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 474 (M+1)⁺

Compound 3921-{3-[7-(2-Hydroxy-ethoxy)-6-methoxy-quinolin-4-yloxy]-quinolin-2-yl}-ethanone

1-{3-[7-(2-Chloro-ethoxy)-6-methoxy-quinolin-4-yloxy]-quinolin-2-yl}-ethanone(37 mg) was dissolved in N,N-dimethylformamide (1 ml) to prepare asolution. Potassium carbonate (363 mg) and water (0.1 ml) were added tothe solution, and the mixture was stirred at 60° C. for 5 days. Waterwas added to the reaction solution, and the mixture was extracted withethyl acetate. The ethyl acetate layer was then washed with saturatedbrine and was dried over anhydrous sodium sulfate. The solvent wasremoved by distillation under the reduced pressure, and the residue waspurified by thin layer chromatography using chloroform-methanol to givethe title compound (2 mg, yield 6%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.78 (s, 3H), 4.05 (s, 3H), 4.09-4.11 (m,2H), 4.32-4.35 (m, 2H), 6.38 (d, J=5.4 Hz, 1H), 7.56 (s, 1H), 7.65 (s,1H), 7.68-7.72 (m, 1H), 7.80-7.85 (m, 2H), 7.99 (s, 1H), 8.25 (d, J=8.3Hz, 1H), 8.45 (d, J=5.4 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 405 (M+1)⁺

Compound 3931-(3-{7-[2-(3-Hydroxy-piperidin-1-yl)-ethoxy]-6-methoxy-quinolin-4-yloxy}-quinolin-2-yl)-ethanone

1-{3-[7-(2-Chloro-ethoxy)-6-methoxy-quinolin-4-yloxy]-quinolin-2-yl}-ethanone(46 mg) was dissolved in N,N-dimethylformamide (1 ml) to prepare asolution. Potassium carbonate (45 mg) and 3-hydroxypiperidine (33 mg)were added to the solution, and the mixture was stirred at 80° C.overnight. Water was added to the reaction solution, and the mixture wasextracted with ethyl acetate. The ethyl acetate layer was then washedwith saturated brine and was dried over anhydrous sodium sulfate. Thesolvent was removed by distillation under the reduced pressure, and theresidue was purified by thin layer chromatography usingchloroform-methanol to give the title compound (37 mg, yield 70%).

¹H-NMR (CDCl₃, 400 MHz): δ 1.63-2.77 (m, 8H), 2.77 (s, 3H), 3.04-3.06(m, 2H), 3.92 (s, 1H), 4.04 (s, 3H), 4.39 (t, J=5.6 Hz, 2H), 6.36 (d,J=5.4 Hz, 1H), 7.47 (s, 1H), 7.63 (s, 1H), 7.67-7.71 (m, 1H), 7.79-8.32(m, 2H), 7.96 (s, 1H), 8.24 (d, J=8.5 Hz, 1H), 8.48 (d, J=5.4 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 488 (M+1)⁺

Compound 3941-[3-(6-Methoxy-7-oxiranylmethoxy-quinolin-4-yloxy)-quinolin-2-yl]-ethanone

1-[3-(7-Hydroxy-6-methoxy-quinolin-4-yloxy)-quinolin-2-yl]-ethanone(compound 390) (200 mg) was dissolved in N,N-dimethylformamide (6 ml) toprepare a solution. Potassium carbonate (230 mg) and epibromohydrin (0.1ml) were added to the solution, and the mixture was stirred at roomtemperature overnight. Water was added to the reaction solution, and themixture was extracted with ethyl acetate. The ethyl acetate layer wasthen washed with saturated brine and was dried over anhydrous sodiumsulfate. The solvent was removed by distillation under the reducedpressure, and the residue was purified by thin layer chromatographyusing chloroform-methanol to give the title compound (152 mg, yield66%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.78 (s, 3H), 2.85-2.88 (m, 1H), 2.96-2.99(m, 1H), 3.50-3.54 (m, 1H), 4.06 (s, 3H), 4.21 (dd, J=5.9 Hz, 11.5 Hz,1H), 4.48 (dd, J=3.2 Hz, 11.2 Hz, 1H), 6.38 (d, J=5.4 Hz, 1H), 7.57 (s,1H), 7.65 (s, 1H), 7.69-7.73 (m, 1H), 7.80-7.85 (m, 2H), 7.99 (s, 1H),8.25 (d, J=9.0 Hz, 1H), 8.47 (d, J=5.6 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 417 (M+1)⁺

Compound 3951-{3-[7-(2,3-Dihydroxy-propoxy)-6-methoxy-quinolin-4-yloxy]-quinolin-2-yl}-ethanone

1-[3-(6-Methoxy-7-oxiranylmethoxy-quinolin-4-yloxy)-quinolin-2-yl]-ethanone(compound 394) (150 mg) was dissolved in methylene chloride (2 ml) toprepare a solution which was brought to 0° C. Trifluoroacetic acid (1ml) was added to the solution, and the mixture was stirred at 0° C. for30 min. The mixture was then stirred at room temperature for 4 hr. Thereaction solution was brought to 0° C. and was stirred. The reactionsolution was made alkaline by the addition of a 10% aqueous sodiumhydroxide solution. Water was added thereto, and the mixture wasextracted with ethyl acetate. The ethyl acetate layer was then washedwith saturated brine and was dried over anhydrous sodium sulfate. Thesolvent was removed by distillation under the reduced pressure, and theresidue was purified by thin layer chromatography usingchloroform-methanol to give the title compound (140 mg, yield 90%).

¹H-NMR (CDCl₃/CD₃OD, 400 MHz): δ 2.78 (s, 3H), 3.82-3.84 (m, 2H), 4.07(s, 3H), 4.19-4.29 (m, 2H), 4.34-4.37 (m, 1H), 6.39 (d, J=5.6 Hz, 1H),7.57 (s, 1H), 7.67 (s, 1H), 7.71-7.75 (m, 1H), 7.82-7.87 (m, 2H), 8.03(s, 1H), 8.26 (d, J=9.3 Hz, 1H), 8.44 (d, J=5.6 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 435 (M+1)

Compound 3961-{3-[7-(3-Hydroxy-2-hydroxymethyl-propoxy)-6-methoxy-quinolin-4-yloxy]-quinolin-2-yl}-ethanone

1-[3-(7-Hydroxy-6-methoxy-quinolin-4-yloxy)-quinolin-2-yl]-ethanone(compound 390) (50 mg) was dissolved in tetrahydrofuran (1 ml) toprepare a solution. Triphenylphosphine (73 mg),(2,2-dimethyl-[1,3]dioxan-5-yl)-methanol (24 mg), anddiethylazodicarboxylate (0.05 ml) were added to the solution, and themixture was stirred at room temperature for 4 hr. Further, 1 N sulfuricacid (3 ml) was added thereto, and the mixture was stirred at roomtemperature overnight. The reaction solution was brought to 0° C. andwas stirred. The reaction solution was made alkaline by the addition ofa 10% aqueous sodium hydroxide solution. Water was added to the reactionsolution, and the mixture was extracted with ethyl acetate. The ethylacetate layer was then washed with saturated brine and was dried overanhydrous sodium sulfate. The solvent was removed by distillation underthe reduced pressure, and the residue was purified by thin layerchromatography using chloroform-methanol to give the title compound (47mg, yield 75%).

¹H-NMR (CDCl₃/CD₃OD, 400 MHz): δ 2.35-2.41 (m, 1H), 2.78 (s, 3H), 3.90(s, 2H), 3.91 (s, 2H), 4.04 (s, 3H), 4.38 (d, J=6.3 Hz, 2H), 6.38 (d,J=5.4 Hz, 1H), 7.51 (s, 1H), 7.65 (s, 1H), 7.71-7.74 (m, 1H), 7.82-7.88(m, 2H), 8.03 (s, 1H), 8.26 (d, J=8.5 Hz, 1H), 8.42 (d, J=5.6 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 449 (M+1)⁺

Compound 3973-(7-Benzyloxy-6-methoxy-quinolin-4-yloxy)-2-methyl-[1,8]naphthyridine

3-Hydroxy-2-methyl-[1,8]naphthyridine (400 mg),7-benzyloxy-4-chloro-6-methoxyquinoline (2.25 g), and4-dimethylaminopyridine (915 mg) were suspended in o-dichlorobenzene (8ml), and the mixture was stirred at 140° C. for 4 hr. The reactionsolution was cooled to room temperature, water was then added to thereaction solution, and the mixture was extracted with chloroform. Thechloroform layer was washed with saturated brine and was dried overanhydrous sodium sulfate. The solvent was removed by distillation underthe reduced pressure, and the residue was purified by columnchromatography using chloroform-methanol to give the title compound (736mg, yield 70%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.76 (s, 3H), 4.05 (s, 3H), 5.36 (s, 2H),6.43 (d, J=5.1 Hz, 1H), 7.32-7.36 (m, 1H), 7.39-7.43 (m, 2H), 7.47-7.55(m, 5H), 7.77 (s, 1H), 8.11 (dd, J=2.0 Hz, 8.3 Hz, 1H), 8.52 (d, J=5.1Hz, 1H), 9.11 (dd, J=2.0 Hz, 4.1 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 424 (M+1)⁺

Compound 3983-[7-(2-Chloro-ethoxy)-6-methoxy-quinolin-4-yloxy]-2-methyl-[1,8]naphthyridine

3-(7-Benzyloxy-6-methoxy-quinolin-4-yloxy)-2-methyl-[1,8]naphthyridine(compound 397) (730 mg) was dissolved in trifluoroacetic acid (7 ml) toprepare a solution. Methanesulfonic acid (0.7 ml) was added to thesolution, and the mixture was stirred at 70° C. for one hr. The reactionsolution was cooled to room temperature, and the solvent was removed bydistillation under the reduced pressure. An aqueous sodiumhydrogencarbonate solution was then added to the residue, and themixture was extracted with chloroform. The chloroform layer was washedwith saturated brine and was dried over anhydrous sodium sulfate. Thesolvent was removed by distillation under the reduced pressure, and theresidue was purified by thin layer chromatography usingchloroform-methanol to give3-[7-hydroxy-6-methoxy-quinolin-4-yloxy]-2-methyl-[1,8]naphthyridine(604 mg, yield 100%).

3-[7-Hydroxy-6-methoxy-quinolin-4-yloxy]-2-methyl-[1,8]naphthyridine (45mg) was dissolved in N,N-dimethylformamide (2 ml) to prepare a solution.Potassium carbonate (187 mg) and 1-bromo-2-chloroethane (0.06 ml) wereadded to the solution, and the mixture was stirred at room temperatureovernight. Water was added to the reaction solution, and the mixture wasextracted with ethyl acetate. The ethyl acetate layer was then washedwith saturated brine and was dried over anhydrous sodium sulfate. Thesolvent was removed by distillation under the reduced pressure, and theresidue was purified by thin layer chromatography usingchloroform-methanol to give the title compound (46 mg, yield 90%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.76 (s, 3H), 3.98 (t, J=6.1 Hz, 2H), 4.05(s, 3H), 4.49 (t, J=6.1 Hz, 2H), 6.45 (d, J=5.4 Hz, 1H), 7.48-7.51 (m,2H), 7.57 (s, 1H), 7.79 (s, 1H), 8.12 (dd, J=1.7 Hz, 8.1 Hz, 1H), 8.55(d, J=5.4 Hz, 1H), 9.12 (dd, J=2.0 Hz, 4.4 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 396 (M+1)⁺

Compound 3991-{2-[6-Methoxy-4-(2-methyl-[1,8]naphthyridin-3-yloxy)-quinolin-7-yloxy]-ethyl}-piperidin-3-ol

3-[7-(2-Chloro-ethoxy)-6-methoxy-quinolin-4-yloxy]-2-methyl-[1,8]naphthyridine(compound 398) (42 mg) was dissolved in N,N-dimethylformamide (2 ml) toprepare a solution. Potassium carbonate (44 mg) and 3-hydroxypiperidine(32 mg) were added to the solution, and the mixture was stirred at 80°C. overnight. The reaction solution was cooled to room temperature, andthe solvent was removed by distillation under the reduced pressure.Water was then added to the residue, and the mixture was extracted withchloroform. The chloroform layer was washed with saturated brine and wasdried over anhydrous sodium sulfate. The solvent was removed bydistillation under the reduced pressure, and the residue was purified bythin layer chromatography using chloroform-methanol to give the titlecompound (29 mg, yield 56%).

¹H-NMR (CDCl₃, 400 MHz): δ 1.62-2.71 (m, 8H), 2.77 (s, 3H), 2.97-3.04(m, 2H), 3.89 (s, 1H), 4.03 (s, 3H), 4.37 (t, J=5.9 Hz, 2H), 6.44 (d,J=5.1 Hz, 1H), 7.47-7.50 (m, 2H), 7.53 (s, 1H), 7.77 (s, 1H), 8.11 (dd,J=2.0 Hz, 8.3 Hz, 1H), 8.54 (d, J=5.4 Hz, 1H), 9.11 (dd, J=2.0 Hz, 4.1Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 461 (M+1)⁺

Compound 4002-[6-Methoxy-4-(2-methyl-[1,8]naphthyridin-3-yloxy)-quinolin-7-yloxy]-ethanol

3-[7-Hydroxy-6-methoxy-quinolin-4-yloxy]-2-methyl-[1,8]naphthyridine(162 mg) was dissolved in N,N-dimethylformamide (5 ml) to prepare asolution. Potassium carbonate (202 mg) and 2-bromoethanol (0.1 ml) wereadded to the solution, and the mixture was stirred at 70° C. overnight.The solvent was removed by distillation under the reduced pressure,water was then added to the residue, and the mixture was extracted withchloroform. The chloroform layer was washed with saturated brine and wasdried over anhydrous sodium sulfate. The solvent was removed bydistillation under the reduced pressure, and the residue was purified bythin layer chromatography using chloroform-acetone to give the titlecompound (130 mg, yield 70%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.77 (s, 3H), 4.04 (s, 3H), 4.10-4.14 (m,2H), 4.34 (t, J=4.6 Hz, 2H), 6.45 (d, J=5.4 Hz, 1H), 7.48-7.51 (m, 1H),7.53 (s, 1H), 7.55 (s, 1H), 7.79 (s, 1H), 8.12 (dd, J=2.0 Hz, 8.1 Hz,1H), 8.54 (d, J=5.1 Hz, 1H), 9.11 (dd, J=2.0 Hz, 4.4 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 378 (M+1)⁺

Compound 4013-(6-Methoxy-7-oxiranylmethoxy-quinolin-4-yloxy)-2-methyl-[1,8]naphthyridine

3-[7-Hydroxy-6-methoxy-quinolin-4-yloxy]-2-methyl-[1,8]naphthyridine(130 mg) was dissolved in N,N-dimethylformamide (4 ml) to prepare asolution. Potassium carbonate (162 mg) and epibromohydrin (0.1 ml) wereadded to the solution, and the mixture was stirred at room temperatureovernight. Water was added to the reaction solution, and the mixture wasextracted with ethyl acetate. The ethyl acetate layer was then washedwith saturated brine and was dried over anhydrous sodium sulfate. Thesolvent was removed by distillation under the reduced pressure, and theresidue was purified by thin layer chromatography usingchloroform-methanol to give the title compound (83 mg, yield 55%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.77 (s, 3H), 2.85-2.87 (m, 1H), 2.96-2.99(m, 1H), 3.50-3.54 (m, 1H), 4.05 (s, 3H), 4.21 (dd, J=5.9 Hz, 11.5 Hz,1H), 4.48 (dd, J=3.4 Hz, 11.5 Hz, 1H), 6.45 (d, J=5.1 Hz, 1H), 7.48-7.52(m, 2H), 7.55 (s, 1H), 7.78 (s, 1H), 8.12 (dd, J=2.0 Hz, 8.1 Hz, 1H),8.54 (d, J=5.4 Hz, 1H), 9.11 (dd, J=2.0 Hz, 4.4 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 390 (M+1)⁺

Compound 4023-[6-Methoxy-4-(2-methyl-[1,8]naphthyridin-3-yloxy)-quinolin-7-yloxy]-propan-1-ol

3-[7-Hydroxy-6-methoxy-quinolin-4-yloxy]-2-methyl-[1,8]naphthyridine (45mg) was dissolved in N,N-dimethylformamide (2 ml) to prepare a solution.Potassium carbonate (56 mg) and 3-bromo-1-propanol (0.04 ml) were addedto the solution, and the mixture was stirred at room temperatureovernight. The solvent was removed by distillation under the reducedpressure. Water was then added to the residue, and the mixture wasextracted with chloroform. The chloroform layer was washed withsaturated brine and was dried over anhydrous sodium sulfate. The solventwas removed by distillation under the reduced pressure, and the residuewas purified by thin layer chromatography using chloroform-acetone togive the title compound (36 mg, yield 71%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.19-2.24 (m, 2H), 2.76 (s, 3H), 3.95 (t,J=5.4 Hz, 2H), 4.03 (s, 3H), 4.42 (t, J=5.9 Hz, 2H), 6.45 (d, J=5.4 Hz,1H), 7.48-7.52 (m, 1H), 7.54 (s, 1H), 7.55 (s, 1H), 7.79 (s, 1H), 8.12(dd, J=2.0 Hz, 8.1 Hz, 1H), 8.54 (d, J=5.4 Hz, 1H), 9.12 (dd, J=2.0 Hz,4.4 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 392 (M+1)⁺

Compound 4033-[6-Methoxy-4-(2-methyl-[1,8]naphthyridin-3-yloxy)-quinolin-7-yloxy]-propane-1,2-diol

3-(6-Methoxy-7-oxiranylmethoxy-quinolin-4-yloxy)-2-methyl-[1,8]naphthyridine(compound 401) (76 mg) was dissolved in methylene chloride (2 ml) toprepare a solution which was then brought to 0° C. Trifluoroacetic acid(0.5 ml) was added to the solution, and the mixture was stirred at 0° C.for 30 min and then at room temperature for 3 hr. The reaction solutionwas brought to 0° C., was stirred, and was made alkaline by the additionof a 10% aqueous sodium hydroxide solution. Water was added thereto, andthe mixture was extracted with chloroform. The chloroform layer was thenwashed with saturated brine and was dried over anhydrous sodium sulfate.The solvent was removed by distillation under the reduced pressure, andthe residue was purified by thin layer chromatography usingchloroform-methanol to give the title compound (46 mg, yield 56%).

¹H-NMR (CDCl₃/CD₃OD, 400 MHz): δ 2.75 (s, 3H), 3.39-3.82 (m, 2H), 4.06(s, 3H), 4.22-4.33 (m, 3H), 6.47 (d, J=5.4 Hz, 1H), 7.48 (s, 1H),7.53-7.58 (m, 2H), 7.86 (s, 1H), 8.19 (d, J=6.6 Hz, 1H), 8.20-8.50 (m,1H), 9.09 (s, 1H)

Mass spectrometric value (ESI−MS, m/z): 408 (M+1)

Compound 4042-[6-Methoxy-4-(2-methyl-[1,8]naphthyridin-3-yloxy)-quinolin-7-yloxymethyl]-propane-1,3-diol

3-[7-Hydroxy-6-methoxy-quinolin-4-yloxy]-2-methyl-[1,8]naphthyridine (85mg) was dissolved in tetrahydrofuran (2 ml) to prepare a solution.Triphenylphosphine (134 mg), (2,2-dimethyl-[1,3]dioxan-5-yl)-methanol(45 mg), and diethylazodicarboxylic acid (0.1 ml) were added to thesolution, and the mixture was stirred at room temperature for 4 hr.Further, 1 N sulfuric acid (4 ml) was added thereto, and the mixture wasstirred at room temperature overnight. The reaction solution was broughtto 0° C., was stirred, and was made alkaline by the addition of a 10%aqueous sodium hydroxide solution. Water was added thereto, and themixture was extracted with ethyl acetate. The ethyl acetate layer wasthen washed with saturated brine and was dried over anhydrous sodiumsulfate. The solvent was removed by distillation under the reducedpressure, and the residue was purified by thin layer chromatographyusing chloroform-methanol to give the title compound (41 mg, yield 39%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.38-2.43 (m, 1H), 2.76 (s, 3H), 4.00-4.01(m, 4H), 4.02 (s, 3H), 4.43 (d, J=5.9 Hz, 2H), 6.45 (d, J=5.1 Hz, 1H),7.48-7.51 (m, 1H), 7.53 (s, 1H), 7.54 (s, 1H), 7.79 (s, 1H), 8.12 (dd,J=2.0 Hz, 8.3 Hz, 1H), 8.53 (d, J=5.4 Hz, 1H), 9.11 (dd, J=2.0 Hz, 4.4Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 422 (M+1)⁺

Compound 4054-[6-Methoxy-4-(2-methyl-[1,8]naphthyridin-3-yloxy)-quinolin-7-yloxy]-butan-1-ol

3-[7-Hydroxy-6-methoxy-quinolin-4-yloxy]-2-methyl-[1,8]naphthyridine (45mg) was dissolved in N,N-dimethylformamide (2 ml) to prepare a solution.Potassium carbonate (56 mg) and 4-bromo-1-butanol (62 mg) were added tothe solution, and the mixture was stirred at room temperature overnight.The solvent was removed by distillation under the reduced pressure.Water was then added to the residue, and the mixture was extracted withchloroform. The chloroform layer was washed with saturated brine and wasdried over anhydrous sodium sulfate. The solvent was removed bydistillation under the reduced pressure, and the residue was purified bythin layer chromatography using chloroform-acetone to give the titlecompound (19 mg, yield 35%).

¹H-NMR (CDCl₃, 400 MHz): δ 1.81-1.88 (m, 2H), 2.05-2.12 (m, 2H), 2.76(s, 3H), 3.78 (t, J=6.1 Hz, 2H), 4.03 (s, 3H), 4.28 (t, J=6.1 Hz, 2H),6.44 (d, J=5.1 Hz, 1H), 7.48-7.51 (m, 2H), 7.53 (s, 1H), 7.78 (s, 1H),8.12 (dd, J=2.0 Hz, 8.1 Hz, 1H), 8.53 (d, J=5.4 Hz, 1H), 9.11 (dd, J=2.0Hz, 4.4 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 404 (M−1)⁻

Compound 4063-(7-Benzyloxy-6-methoxy-quinolin-4-yloxy)-2-methyl-[1,6]naphthyridine

3-Hydroxy-2-methyl-[1,6]naphthyridine (400 mg),7-benzyloxy-4-chloro-6-methoxyquinoline (2.25 g), and4-dimethylaminopyridine (915 mg) were suspended in o-dichlorobenzene (8ml), and the suspension was stirred at 140° C. for 4 hr. The reactionsolution was cooled to room temperature, water was then added to thereaction solution, and the mixture was extracted with chloroform. Thechloroform layer was washed with saturated brine and was dried overanhydrous sodium sulfate. The solvent was removed by distillation underthe reduced pressure, and the residue was purified by columnchromatography using chloroform-methanol to give the title compound (597mg, yield 56%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.75 (s, 3H), 4.05 (s, 3H), 5.36 (s, 2H),6.44 (d, J=5.1 Hz, 1H), 7.32-7.36 (m, 1H), 7.39-7.43 (m, 2H), 7.52 (s,2H), 7.54 (s, 2H), 7.85 (s, 1H), 7.91 (d, J=6.1 Hz, 1H), 8.53 (d, J=5.4Hz, 1H), 8.76 (d, J=6.1 Hz, 1H), 9.18 (d, J=1.0 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 424 (M+1)⁺

Compound 4072-[6-Methoxy-4-(2-methyl-[1,6]naphthyridin-3-yloxy)-quinolin-7-yloxy]-ethanol

3-(7-Benzyloxy-6-methoxy-quinolin-4-yloxy)-2-methyl-[1,6]naphthyridine(compound 406) (590 mg) was dissolved in trifluoroacetic acid (6 ml) toprepare a solution. Methanesulfonic acid (0.6 ml) was added to thesolution, and the mixture was stirred at 70° C. for one hr. The reactionsolution was cooled to room temperature, and the solvent was removed bydistillation under the reduced pressure. An aqueous sodiumhydrogencarbonate solution was then added to the residue, and themixture was extracted with chloroform. The chloroform layer was washedwith saturated brine and was dried over anhydrous sodium sulfate. Thesolvent was removed by distillation under the reduced pressure, and theresidue was purified by thin layer chromatography usingchloroform-methanol to give3-(7-hydroxy-6-methoxy-quinolin-4-yloxy)-2-methyl-[1,6]naphthyridine(456 mg, yield 98%).

3-(7-Hydroxy-6-methoxy-quinolin-4-yloxy)-2-methyl-[1,6]naphthyridine(157 mg) was dissolved in N,N-dimethylformamide (8 ml) to prepare asolution. Potassium carbonate (195 mg) and 2-bromoethanol (0.1 ml) wereadded to the solution, and the mixture was stirred at 70° C. overnight.The solvent was removed by distillation under the reduced pressure.Water was then added to the residue, and the mixture was extracted withchloroform. The chloroform layer was washed with saturated brine and wasdried over anhydrous sodium sulfate. The solvent was removed bydistillation under the reduced pressure, and the residue was purified bythin layer chromatography using chloroform-acetone to give the titlecompound (147 mg, yield 83%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.75 (s, 3H), 4.04 (s, 3H), 4.12 (t, J=4.4Hz, 2H), 4.34 (t, J=4.9 Hz, 2H), 6.46 (d, J=5.4 Hz, 1H), 7.54 (d, J=1.5Hz, 2H), 7.88 (s, 1H), 7.91 (d, J=6.1 Hz, 1H), 8.55 (d, J=5.1 Hz, 1H),8.77 (d, J=5.9 Hz, 1H), 9.19 (s, 1H)

Mass spectrometric value (ESI−MS, m/z): 378 (M+1)⁺

Compound 4083-[6-Methoxy-4-(2-methyl-[1,6]naphthyridin-3-yloxy)-quinolin-7-yloxy]-propane-1,2-diol

3-(7-Hydroxy-6-methoxy-quinolin-4-yloxy)-2-methyl-[1,6]naphthyridine(126 mg) was dissolved in N,N-dimethylformamide (8 ml) to prepare asolution. Potassium carbonate (156 mg) and epibromohydrin (0.1 ml) wereadded to the solution, and the mixture was stirred at room temperatureovernight. Water was added to the reaction solution, and the mixture wasextracted with ethyl acetate. The ethyl acetate layer was then washedwith saturated brine and was dried over anhydrous sodium sulfate. Thesolvent was removed by distillation under the reduced pressure, and theresidue was purified by thin layer chromatography usingchloroform-methanol to give3-(6-methoxy-7-oxiranylmethoxy-quinolin-4-yloxy)-2-methyl-[1,6]naphthyridine(48 mg, yield 33%).

3-(6-Methoxy-7-oxiranylmethoxy-quinolin-4-yloxy)-2-methyl-[1,6]naphthyridine(44 mg) was dissolved in methylene chloride (2 ml) to prepare a solutionwhich was brought to 0° C. Trifluoroacetic acid (0.4 ml) was addedthereto, and the mixture was stirred at 0° C. for 30 min and then atroom temperature for 4 hr. The reaction solution was brought to 0° C.,was stirred, and was made alkaline by the addition of a 10% aqueoussodium hydroxide solution. Water was added thereto, and the mixture wasextracted with chloroform. The chloroform layer was then washed withsaturated brine and was dried over anhydrous sodium sulfate. The solventwas removed by distillation under the reduced pressure, and the residuewas purified by thin layer chromatography using chloroform-methanol togive the title compound (7 mg, yield 15%).

¹H-NMR (CD₃OD, 400 MHz): δ 2.74 (s, 3H), 3.71-3.80 (m, 2H), 4.03 (s,3H), 4.11-4.31 (m, 3H), 6.66 (d, J=5.4 Hz, 1H), 7.45 (s, 1H), 7.68 (s,1H), 7.96 (d, J=6.1 Hz, 1H), 8.26 (s, 1H), 8.49 (d, J=5.4 Hz, 1H), 8.70(d, J=6.1 Hz, 1H), 9.26 (s, 1H)

Mass spectrometric value (ESI−MS, m/z): 408 (M+1)⁺

Compound 4092-[6-Methoxy-4-(2-methyl-[1,6]naphthyridin-3-yloxy)-quinolin-7-yloxymethyl]-propane-1,3-diol

3-(7-Hydroxy-6-methoxy-quinolin-4-yloxy)-2-methyl-[1,6]naphthyridine (85mg) was dissolved in tetrahydrofuran (2 ml) to prepare a solution.Triphenylphosphine (134 mg), (2,2-dimethyl-[1,3]dioxan-5-yl)-methanol(45 mg), and diethylazodicarboxylic acid (0.1 ml) were added to thesolution, and the mixture was stirred at room temperature for 4 hr.Further, 1 N sulfuric acid (4 ml) was added thereto, and the mixture wasstirred at room temperature overnight. The reaction solution was broughtto 0° C., was stirred, and was made alkaline by the addition of a 10%aqueous sodium hydroxide solution. Water was added thereto, and themixture was extracted with ethyl acetate. The ethyl acetate layer wasthen washed with saturated brine and was dried over anhydrous sodiumsulfate. The solvent was removed by distillation under the reducedpressure, and the residue was purified by thin layer chromatographyusing chloroform-methanol to give the title compound (66 mg, yield 63%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.38-2.43 (m, 1H), 2.74 (s, 3H), 4.00-4.01(m, 4H), 4.02 (s, 3H), 4.43 (d, J=5.6 Hz, 2H), 6.46 (d, J=5.1 Hz, 1H),7.52 (s, 1H), 7.55 (s, 1H), 7.87 (s, 1H), 7.91 (d, J=5.9 Hz, 1H), 8.55(d, J=5.1 Hz, 1H), 8.77 (d, J=5.9 Hz, 1H), 9.19 (s, 1H)

Mass spectrometric value (ESI−MS, m/z): 422 (M+1)⁺

Compound 410[6-Methoxy-4-(2-methyl-quinolin-3-yloxy)-quinolin-7-yl]-(2-morpholin-4-yl-ethyl)-amine

Palladium acetate (62 mg) and2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (170 mg) were dissolved intoluene (16 ml) to prepare a solution which was then stirred at roomtemperature for 5 min. 4-Chloro-6-methoxy-quinolin-7-yltrifluoro-methanesulfonate (400 mg) and 2-morpholin-4-yl-ethylamine(1.12 ml) were added thereto, and the mixture was further stirred atroom temperature for 5 min. Cesium carbonate (1.97 g) was added to thereaction solution, and the mixture was stirred at 90° C. overnight.Water was added to the reaction solution, and the mixture was extractedwith chloroform. The chloroform layer was then washed with water and wasdried over anhydrous sodium sulfate. The solvent was removed bydistillation under the reduced pressure, and the residue was purified bythin layer chromatography using methanol chloroform to give(4-chloro-6-methoxy-quinolin-7-yl)-(2-morpholin-4-yl-ethyl)-amine (53mg, yield 14%).

(4-Chloro-6-methoxy-quinolin-7-yl)-(2-morpholin-4-yl-ethyl)-amine (53mg), 3-hydroxy-2-methyl-quinolin-4-carboxylic acid (126 mg), and4-dimethylaminopyridine (200 mg) were suspended in o-dichlorobenzene (8ml). The suspension was stirred at 140° C. overnight. The reactionsolution was cooled to room temperature, and the solvent was removed bydistillation under the reduced pressure. Water was then added to theresidue, and the mixture was extracted with ethyl acetate. The ethylacetate layer was washed with water and was dried over anhydrous sodiumsulfate. The solvent was removed by distillation under the reducedpressure, and the residue was purified by column chromatography usingmethanol-chloroform to give the title compound (12 mg, yield 16%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.53 (s, 3H), 2.68 (s, 3H), 2.76 (m, 2H),3.38 (m, 2H), 3.76 (m, 4H), 4.04 (s, 3H), 5.41 (m, 1H), 6.28 (d, J=5.4Hz, 1H), 7.08 (s, 1H), 7.44 (s, 1H), 7.53 (m, 1H), 7.68-7.74 (m, 2H),7.76 (s, 1H), 8.09 (d, J=8.6 Hz, 1H), 8.42 (d, J=5.4 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 445 (M+1)⁺

Compound 4113-[6-Methoxy-4-(2-methyl-quinolin-3-yloxy)-quinolin-7-yl]-propan-1-ol

Ethyl 3-[6-methoxy-4-(2-methyl-quinolin-3-yloxy)-quinolin-7-yl]-acrylate(compound 413) (310 mg) was dissolved intriethylamine/N,N-dimethylformamide (2.5 ml/13 ml) to prepare asolution. 20% palladium hydroxide (1.27 g) was added to the solution,and the mixture was stirred under a hydrogen gas atmosphere at roomtemperature overnight. The reaction solution was filtered, and thesolvent was then removed by distillation under the reduced pressure.Water was added to the residue, and the mixture was extracted with ethylacetate. The ethyl acetate layer was then washed with water and wasdried over anhydrous sodium sulfate. The solvent was removed bydistillation under the reduced pressure, and the residue was purified bythin layer chromatography using acetone-chloroform to give ethyl3-[6-methoxy-4-(2-methyl-quinolin-3-yloxy)-quinolin-7-yl]-propionate (80mg, yield 26%).

Ethyl3-[6-methoxy-4-(2-methyl-quinolin-3-yloxy)-quinolin-7-yl]-propionate (80mg) was dissolved in tetrahydrofuran (5 ml) to prepare a solution. Adiisobutylaluminum hydride/0.93 M hexane solution (1 ml) was added tothe solution under ice cooling, and the mixture was stirred at roomtemperature for 3 hr. Water was added to the reaction solution, and themixture was extracted with ethyl acetate. The ethyl acetate layer wasthen washed with water and was dried over anhydrous sodium sulfate. Thesolvent was removed by distillation under the reduced pressure, and theresidue was purified by column chromatography using acetone-chloroformto give the title compound (50 mg, yield 69%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.02 (m, 2H), 2.67 (s, 3H), 2.96 (t, J=7.3Hz, 2H), 3.74 (t, J=6.4 Hz, 2H), 4.02 (s, 3H), 6.42 (d, J=5.1 Hz, 1H),7.55 (m, 1H), 7.58 (s, 1H), 7.70-7.77 (m, 2H), 7.81 (s, 1H), 7.91 (s,1H), 8.10 (d, J=8.3 Hz, 1H), 8.53 (d, J=5.4 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 375 (M+1)⁺

Compound 4126-Methoxy-4-(2-methyl-quinolin-3-yloxy)-7-(3-morpholin-4-yl-propyl)-quinoline

3-[6-Methoxy-4-(2-methyl-quinolin-3-yloxy)-quinolin-7-yl]-propan-1-ol(compound 411) (23 mg) was dissolved in triethylamine/dichloromethane (1ml/4 ml) to prepare a solution. Methanesulfonyl chloride (0.2 ml) wasadded to the solution, and the mixture was stirred at room temperaturefor 5 min. The solvent was removed by distillation under the reducedpressure, and the residue was used in the next reaction withoutpurification.

The residue was dissolved in N,N-dimethylformamide (4 ml) to prepare asolution. Potassium carbonate (230 mg) and morpholine (0.2 ml) wereadded to the solution, and the mixture was stirred at 70° C. for 3 days.Water was added to the reaction solution, and the mixture was extractedwith ethyl acetate. The ethyl acetate layer was then washed with waterand was dried over anhydrous sodium sulfate. The solvent was removed bydistillation under the reduced pressure, and the residue was purified bythin layer chromatography using acetone-chloroform to give the titlecompound (17 mg, yield 63%).

¹H-NMR (CDCl₃, 400 MHz): δ 1.93 (m, 2H), 2.45-2.49 (m, 6H), 2.67 (s,3H), 2.88 (t, J=7.6 Hz, 2H), 3.74 (m, 4H), 4.00 (s, 3H), 6.42 (d, J=5.1Hz, 1H), 7.52-7.56 (m, 2H), 7.70-7.76 (m, 2H), 7.81 (s, 1H), 7.88 (s,1H), 8.10 (d, J=8.6 Hz, 1H), 8.52 (d, J=4.9 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 444 (M+1)⁺

Compound 413 Ethyl3-[6-methoxy-4-(2-methyl-quinolin-3-yloxy)-quinolin-7-yl]-acrylate

Palladium acetate (28 mg), 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl(80 mg) was dissolved in N,N-dimethylformamide (2 ml) to prepare asolution, and the mixture was stirred at room temperature for 5 min.4-Chloro-6-methoxy-quinolin-7-yl trifluoro-methanesulfonate (100 mg) andethyl acrylate (0.08 ml) were added thereto, and the mixture was furtherstirred at room temperature for 5 min. Triethylamine (0.12 ml) was addedto the reaction solution, and the mixture was stirred at 80° C. for 6hr. Water was added to the reaction solution, and the mixture wasextracted with ethyl acetate. The ethyl acetate layer was then washedwith water and was dried over anhydrous sodium sulfate. The solvent wasremoved by distillation under the reduced pressure, and the residue wasused in the next reaction without purification.

The residue, 3-hydroxy-2-methyl-quinoline (63 mg), and4-dimethylaminopyridine (175 mg) were suspended in o-dichlorobenzene (3ml), and the mixture was stirred at 130° C. for 2 days. The reactionsolution was cooled to room temperature, and the solvent was removed bydistillation under the reduced pressure. Water was then added to theresidue, and the mixture was extracted with ethyl acetate. The ethylacetate layer was washed with water and was dried over anhydrous sodiumsulfate. The solvent was removed by distillation under the reducedpressure, and the residue was purified by thin layer chromatographyusing acetone-chloroform to give the title compound (28 mg, yield 23%)(2 steps).

¹H-NMR (CDCl₃, 400 MHz): δ 1.38 (t, J=6.1 Hz, 3H), 2.66 (s, 3H), 4.07(s, 3H), 4.32 (q, J=7.1 Hz, 2H), 6.44 (d, J=5.1 Hz, 1H), 6.77 (d, J=16.4Hz, 1H), 7.56 (m, 1H), 7.65 (s, 1H), 7.71-7.78 (m, 3H), 7.84 (s, 1H),8.14 (d, J=16.1 Hz, 1H), 8.29 (s, 1H), 8.57 (d, J=4.9 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 415 (M+1)⁺

Compound 4146-Methoxy-4-(2-methyl-quinolin-3-yloxy)-7-pyridin-4-yl-quinoline

4-Chloro-6-methoxy-quinolin-7-yl trifluoro-methanesulfonate (114 mg),4-pyridine boranic acid (55 mg), and tetrakistriphenylphosphinepalladium (30 mg) were dissolved in N,N-dimethylformamide (4 ml) toprepare a solution. A 2 M aqueous potassium carbonate solution (0.3 ml)was added to the reaction system, and the mixture was stirred at 80° C.for 2 hr. Water was added to the reaction solution, and the mixture wasextracted with ethyl acetate. The ethyl acetate layer was then washedwith water and was dried over anhydrous sodium sulfate. The solvent wasremoved by distillation under the reduced pressure, and the residue (84mg) was used in the next reaction without purification.

A part (58 mg) of the residue, 3-hydroxy-2-methyl-quinoline-4-carboxylicacid (124 mg), and 4-dimethylaminopyridine (120 mg) were dissolved ino-dichlorobenzene (5 ml), and the solution was stirred at 130° C.overnight and further at 160° C. for 4 hr. The reaction solution wascooled to room temperature, water was then added to the reactionsolution, and the mixture was extracted with ethyl acetate. The ethylacetate layer was then washed with water and was dried over anhydroussodium sulfate. The solvent was removed by distillation under thereduced pressure, and the residue was purified by thin layerchromatography using acetone-chloroform to give the title compound (14mg, yield 16%) (2 steps).

¹H-NMR (CDCl₃, 400 MHz): δ 2.68 (s, 3H), 4.03 (s, 3H), 6.49 (d, J=5.1Hz, 1H), 7.55-7.62 (m, 3H), 7.73-7.81 (m, 3H), 7.87 (s, 1H), 8.12 (s,1H), 8.13 (m, 1H), 8.60 (d, J=5.1 Hz, 1H), 8.72 (d, J=5.9 Hz, 2H)

Mass spectrometric value (ESI−MS, m/z): 394 (M+1)⁺

Compound 4156-Benzyloxy-7-methoxy-4-(2-methyl-quinolin-3-yloxy)-quinoline

3-Hydroxy-2-methyl-4-quinoline carboxylic acid (549 mg),6-benzyloxy-4-chloro-7-methoxyquinoline (810 mg), and4-(N,N-dimethylamino)-pyridine (990 mg) were dissolved in1,2-dichlorobenzene (40 ml) to prepare a solution. The mixture wasstirred at 150° C. overnight. The reaction solution was cooled to roomtemperature, and the solvent was then removed by distillation under thereduced pressure. Water was added to the residue, and the mixture wasextracted with chloroform. The chloroform layer was washed with waterand was then dried over anhydrous sodium sulfate. The solvent wasremoved by distillation under the reduced pressure, and the residue waspurified by column chromatography using hexane-acetone to give the titlecompound (718 mg, yield 63%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.61 (s, 3H), 4.06 (s, 3H), 5.32 (s, 2H),6.41 (d, J=5.1 Hz, 1H), 7.22-7.40 (m, 3H), 7.44-7.58 (m, 4H), 7.61 (s,1H), 7.67-7.76 (m, 3H), 8.09 (d, J=8.3 Hz, 1H), 8.51 (d, J=5.1 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 423 (M+1)⁺

Compound 4166-(2-Imidazol-1-yl-ethoxy)-7-methoxy-4-(2-methyl-quinolin-3-yloxy)-quinoline

Trifluoroacetic acid (5 ml) and methanesulfonic acid (0.2 ml) were addedto 6-benzyloxy-7-methoxy-4-(2-methyl-quinolin-3-yloxy)-quinoline(compound 415) (700 mg), and the mixture was stirred at 100° C. for 2hr. The reaction solution was cooled to room temperature, and thesolvent was then removed by distillation under the reduced pressure. Asaturated aqueous sodium hydrogencarbonate solution was added to theresidue, and the mixture was extracted with chloroform. The chloroformlayer was washed with a saturated aqueous sodium hydrogencarbonatesolution and water and was then dried over anhydrous magnesium sulfate.The solvent was removed by distillation under the reduced pressure, andthe residue was purified by column chromatography usingchloroform-methanol to give7-methoxy-4-(2-methyl-quinolin-3-yloxy)-quinolin-6-ol (26 mg, yield 5%).

7-Methoxy-4-(2-methyl-quinolin-3-yloxy)-quinolin-6-ol (25 mg) wasdissolved in N,N-dimethylformamide (1 ml) to prepare a solution.1-Bromo-2-chloroethane (54 mg) and potassium carbonate (52 mg) wereadded to the solution, and the mixture was stirred at room temperatureovernight. Water was added to the reaction solution, and the mixture wasextracted with chloroform. The chloroform layer was washed with waterand was then dried over anhydrous magnesium sulfate. The solvent wasremoved by distillation under the reduced pressure. The residue waspurified by thin layer chromatography using chloroform-methanol to give6-(2-chloro-ethoxy)-7-methoxy-4-(2-methyl-quinolin-3-yloxy)-quinoline(24 mg, yield 79%).

N,N-Dimethylformamide (3 ml) was added to6-(2-chloro-ethoxy)-7-methoxy-4-(2-methyl-quinolin-3-yloxy)-quinoline(24 mg), potassium carbonate (25 mg), imidazole (12 mg), and sodiumiodide (1.8 mg), and the mixture was stirred at 75° C. overnight. Thereaction solution was cooled to room temperature, and the solvent wasremoved by distillation under the reduced pressure. Water was added tothe residue, and the mixture was extracted with chloroform. Thechloroform layer was washed with water and was then dried over anhydroussodium sulfate. The solvent was removed by distillation under thereduced pressure. The residue was purified by thin layer chromatographyusing chloroform-methanol to give the title compound (9.2 mg, yield36%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.62 (s, 3H), 4.06 (s, 3H), 4.39-4.54 (m,4H), 6.36 (d, J=5.2 Hz, 1H), 7.08 (s, 1H), 7.15 (s, 1H), 7.48 (s, 1H),7.50-7.59 (m, 2H), 7.68-7.78 (m, 3H), 7.79 (s, 1H), 8.10 (d, J=8.1 Hz,1H), 8.51 (d, J=5.4 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 449 (M+Na)⁺

Compound 4173-[7-Methoxy-4-(2-methyl-quinolin-3-yloxy)-quinolin-6-yloxy]-propane-1,2-diol

N,N-Dimethylformamide (6 ml) was added to7-methoxy-4-(2-methyl-quinolin-3-yloxy)-quinolin-6-ol (189 mg),potassium carbonate (236 mg), and epibromohydrin (234 mg), and themixture was stirred at room temperature overnight. Water was added tothe reaction solution, and the mixture was extracted with ethyl acetate.The ethyl acetate layer was washed with water and was then dried overanhydrous sodium sulfate. The solvent was removed by distillation underthe reduced pressure, and the residue was purified by thin layerchromatography using hexane-acetone to give7-methoxy-4-(2-methyl-quinolin-3-yloxy)-6-oxiranylmethoxy-quinoline (59mg, yield 27%).

7-Methoxy-4-(2-methyl-quinolin-3-yloxy)-6-oxiranylmethoxy-quinoline (59mg) was dissolved in dichloromethane (2 ml) to prepare a solution.Trifluoroacetic acid (2 ml) was added dropwise to the solution at 0° C.,and the mixture was then stirred at room temperature for 4 hr. Thereaction solution was made alkaline by the addition of 1 N sodiumhydroxide, and the mixture was extracted with chloroform. The chloroformlayer was washed with water and was then dried over anhydrous sodiumsulfate. The solvent was removed by distillation under the reducedpressure, and the residue was purified by thin layer chromatographyusing chloroform-methanol to give the title compound (18 mg, yield 29%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.64 (s, 3H), 3.85-3.95 (m, 2H), 4.04 (s,3H), 4.19-4.32 (m, 2H), 4.35 (dd, J=3.6, 9.3 Hz, 1H), 6.37 (d, J=5.4 Hz,1H), 7.50 (s, 1H), 4.55 (dd, J=7.8, 7.8 Hz, 1H), 7.64 (s, 1H), 7.72 (dd,J=1.2, 8.3 Hz, 1H), 7.76 (d, J=8.5 Hz, 1H), 7.81 (s, 1H), 8.11 (d, J=8.3Hz, 1H), 8.51 (d, J=5.2 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 429 (M+Na)⁺

Compound 418 (6,7-Dimethoxy-quinolin-4-yl)-quinolin-3-yl-amine

4-Chloro-6,7-dimethoxyquinoline (88 mg) and 3-aminoquinoline (72 mg)were dissolved in dimethylacetamide (1 ml) to prepare a solution. 60%sodium hydride (46 mg) was added to the solution under ice cooling. Themixture was stirred at 80° C. for 2 hr. Water was then added to thereaction solution, and the mixture was extracted with ethyl acetate. Theethyl acetate layer was dried over anhydrous sodium sulfate. The solventwas removed by distillation under the reduced pressure, and the residuewas purified by column chromatography using methanol-chloroform to givethe title compound (37 mg, yield 28%).

¹H-NMR (CDCl₃, 400 MHz): δ 3.98 (s, 3H), 3.99 (s, 3H), 6.96 (d, J=5.4Hz, 1H), 7.24 (s, 1H), 7.39 (s, 1H), 7.54 (m, 1H), 7.64 (m, 1H), 7.73(d, J=8.0 Hz, 1H), 7.96 (d, J=2.5 Hz, 1H), 8.08 (d, J=5.4 Hz, 1H), 8.43(d, J=5.4 Hz, 1H), 8.90 (d, J=2.7 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 332 (M+1)⁺

Compound 419 Ethyl2-(6,7-dimethoxy-quinolin-4-ylsulfanyl)-5-fluoro-benzoate

5-Fluoro-2-mercaptobenzoic acid (278 mg) and4-chloro-6,7-dimethoxyquinoline (300 mg) were suspended in acetonitrile(6 ml), and the suspension was stirred at room temperature overnight.The solvent was removed by distillation under the reduced pressure.Water was added to the residue, the mixture was neutralized with sodiumhydrogencarbonate and was then extracted with chloroform. The chloroformlayer was washed with water and saturated brine and was dried overanhydrous magnesium sulfate. The solvent was removed by distillationunder the reduced pressure, and the residue was purified by columnchromatography using chloroform-methanol to give2-(6,7-dimethoxy-quinolin-4-ylsulfanyl)-5-fluoro-benzoic acid (152 mg,yield 31%).

2-(6,7-Dimethoxy-quinolin-4-ylsulfanyl)-5-fluoro-benzoic acid (76 mg)was suspended in ethanol (387 mg), and the suspension was cooled at 0°C. Thionyl chloride (50 mg) was gradually added dropwise thereto, andthe mixture was then heated under reflux for 20 min. The solvent wasremoved by distillation under the reduced pressure, water was added tothe residue, and the mixture was neutralized with a 20% aqueous sodiumhydroxide solution and was then extracted with ethyl acetate. Next, theethyl acetate layer was washed with water and saturated brine and wasdried over anhydrous sodium sulfate. The solvent was removed bydistillation under the reduced pressure, and the residue was purified bycolumn chromatography using acetone-hexane to give the title compound(68 mg, 84%).

¹H-NMR (CDCl₃, 400 MHz): δ 1.25 (t, J=7.2 Hz, 3H), 3.82 (s, 3H), 3.95(s, 3H), 4.30 (q, J=7.2 Hz, 2H), 6.81-6.95 (m, 2H), 7.15 (d, J=4.8 Hz,1H), 7.31 (s, 1H), 7.36 (s, 1H), 7.60 (dd, J=8.8 Hz, 3.2 Hz, 1H), 8.52(d, J=4.8 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 388 (M+1)⁺

Compound 420 6,7-Dimethoxy-4-(quinolin-2-ylsulfanyl)-quinoline

2-Quinolinethiol (87 mg) and 4-chloro-6,7-dimethoxyquinoline (100 mg)were suspended in acetonitrile (3 ml), and the suspension was stirred atroom temperature overnight. The solvent was removed by distillationunder the reduced pressure. Water was added to the residue, and themixture was neutralized with sodium hydrogencarbonate and was thenextracted with chloroform. The chloroform layer was washed with waterand saturated brine and was dried over anhydrous magnesium sulfate. Thesolvent was removed by distillation under the reduced pressure, and theresidue was purified by column chromatography using acetone-chloroformto give the title compound (15 mg, yield 10%).

¹H-NMR (CDCl₃, 400 MHz): δ 3.77 (s, 3H), 3.99 (s, 3H), 6.92 (d, J=8.8Hz, 1H), 7.38-7.48 (m, 3H), 7.52 (d, J=4.8 Hz, 1H), 7.59-7.69 (m, 2H),7.84 (d, J=8.4 Hz, 1H), 7.90 (d, J=8.4 Hz, 1H), 8.63 (d, J=4.8 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 349 (M+1)⁺

Compound 4213-(6,7-Dimethoxy-quinolin-4-yloxy)-2-pyridin-2-yl-[1,8]naphthyridine

2-Aminopyridine (14.1 g) and triethylamine (19.0 g) were dissolved indichloromethane (200 ml) to prepare a solution which was cooled to 0° C.A solution of pivaloyl chloride (19.9 g) in dichloromethane (30 ml) wasgradually added dropwise thereto, and the mixture was stirred at 0° C.for 15 min. Thereafter, the reaction solution was stirred at roomtemperature for 4 hr. The reaction solution was poured into water (150ml), and the dichloromethane layer was washed with a dilute aqueoussodium hydrogencarbonate solution and was dried over anhydrous sodiumsulfate. The solvent was removed by distillation under the reducedpressure, and the residue was purified by column chromatography usingchloroform to give 2,2-dimethyl-N-pyridin-2-yl-propionamide (25.2 g,yield 95%).

2,2-Dimethyl-N-pyridin-2-yl-propionamide (20.3 g) was dissolved intetrahydrofuran (230 ml) to prepare a solution which was cooled to −78°C. A 2.44 M n-butyllithium/n-hexane solution (100 ml) was graduallyadded dropwise thereto, and the mixture was stirred at −78° C. for 15min. The reaction solution was stirred at 0° C. for 2 hr and was thenagain cooled to −78° C. A solution of N,N-dimethylformamide (25.0 g) intetrahydrofuran (25 ml) was gradually added dropwise thereto. Thetemperature of the reaction solution was raised to room temperature. Thereaction solution was then poured into a mixture of ice (50 g) with 6 Nhydrochloric acid (150 ml), and the mixture was stirred at roomtemperature for 20 min. The aqueous layer was neutralized with potassiumcarbonate powder and was extracted with diethyl ether, and the diethylether layer was then washed with water and saturated brine and was driedover magnesium sulfate. The solvent was removed by distillation underthe reduced pressure, and the residue was purified by columnchromatography using acetone-chloroform to giveN-(3-formyl-pyridin-2-yl)-2,2-dimethyl-propionamide (11.8 g, yield 50%).

N-(3-Formyl-pyridin-2-yl)-2,2-dimethyl-propionamide (9.68 g) wasdissolved in 3 N hydrochloric acid (140 ml), and the solution wasstirred under reflux overnight. The reaction solution was cooled to roomtemperature, was then washed with diethyl ether, and was neutralizedwith potassium carbonate powder. Diethyl ether was added thereto, andthe mixture was extracted. The diethyl ether layer was dried overpotassium carbonate, and the solvent was removed by distillation underthe reduced pressure. The residue was purified by column chromatographyusing acetone-chloroform to give 2-amino-pyridine-3-carbaldehyde (5.03g, yield 88%).

2-Amino-pyridine-3-carbaldehyde (200 mg) and 2-(bromoacetyl)pyridinehydrobromide (506 mg) were suspended in a 5 N aqueous sodium hydroxidesolution (1 ml), and the suspension was hermetically sealed and, in thisstate, was allowed to stand for 2 days. The reaction solution wasneutralized with 10% hydrochloric acid, dichloromethane was then addedthereto, and the mixture was extracted. The dichloromethane layer waswashed with water and saturated brine and was dried over magnesiumsulfate. The solvent was removed by distillation under the reducedpressure, and the residue was purified by column chromatography usingchloroform-methanol to give 2-pyridin-2-yl-[1,8]naphthyridin-3-ol (48mg, yield 13%).

2-Pyridin-2-yl-[1,8]naphthyridin-3-ol (9 mg),4-chloro-6,7-dimethoxyquinoline (27 mg), and 4-dimethylaminopyridine (16mg) were suspended in o-dichlorobenzene (1.5 ml), and the mixture wasstirred at 140° C. for 48 hr. The reaction solution was cooled to roomtemperature, water was then added to the reaction solution, and themixture was extracted with chloroform. The chloroform layer was thenwashed with water and saturated brine and was dried over anhydrousmagnesium sulfate. The solvent was removed by distillation under thereduced pressure, and the residue was purified by thin layerchromatography using chloroform-methanol to give the title compound (2mg, yield 12%).

¹H-NMR (CDCl₃, 400 MHz): δ 3.97 (s, 3H), 3.98 (s, 3H), 6.39 (d, J=5.2Hz, 1H), 7.12 (m, 1H), 7.35 (s, 1H), 7.50 (dd, J=8.0, 4.0 Hz, 1H), 7.61(s, 1H), 7.69 (ddd, J=9.6, 8.0, 1.6 Hz, 1H), 7.98 (s, 1H), 8.14 (m, 2H),8.29 (d, J=4.4 Hz, 1H), 8.36 (d, J=5.2 Hz, 1H), 9.12 (dd, J=4.0, 2.0 Hz,1H)

Mass spectrometric value (ESI−MS, m/z): 433 (M+Na)⁺

Compound 4223-(6,7-Dimethoxy-quinolin-4-yloxy)-2-phenyl-[1,8]naphthyridine

2-Amino-pyridine-3-carbaldehyde (100 mg) and 2-chloro-1-phenyl-ethanone(127 mg) were suspended in a 5 N aqueous sodium hydroxide solution (0.6ml), and the suspension was hermetically sealed and, in this state, wasallowed to stand for 3 days. The reaction solution was neutralized with10% hydrochloric acid. Dichloromethane was then added thereto, and themixture was extracted. The dichloromethane layer was washed with waterand saturated brine and was dried over magnesium sulfate. The solventwas removed by distillation under the reduced pressure, and the residuewas purified by column chromatography using chloroform-methanol to give2-phenyl-[1,8]naphthyridin-3-ol (23 mg, yield 13%).

2-Phenyl-[1,8]naphthyridin-3-ol (23 mg), 4-chloro-6,7-dimethoxyquinoline(69 mg), and 4-dimethylaminopyridine (38 mg) were suspended ino-dichlorobenzene (2 ml), and the mixture was stirred at 140° C. for 5.5hr. The reaction solution was cooled to room temperature. Water was thenadded to the reaction solution, and the mixture was extracted withchloroform. The chloroform layer was then washed with water andsaturated brine and was dried over anhydrous magnesium sulfate. Thesolvent was removed by distillation under the reduced pressure, and theresidue was purified by thin layer chromatography usingchloroform-methanol to give the title compound (29 mg, yield 71%).

¹H-NMR (CDCl₃, 400 MHz): δ 3.93 (s, 3H), 3.97 (s, 3H), 6.44 (d, J=5.2Hz, 1H), 7.29 (m, 3H), 7.37 (s, 1H), 7.40 (s, 1H), 7.50 (dd, J=8.0, 3.6Hz, 1H), 7.85 (s, 1H), 8.08 (m, 3H), 8.41 (d, J=5.2 Hz, 1H), 9.08 (dd,J=4.0, 1.6 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 410 (M+1)⁺

Compound 4233-(6,7-Dimethoxy-quinolin-4-yloxy)-2-ethyl-[1,8]naphthyridine

2-Amino-pyridine-3-carbaldehyde (100 mg) and 1-bromo-butan-2-one (124mg) were suspended in a 5 N aqueous sodium hydroxide solution (0.6 ml),and the suspension was hermetically sealed and, in this state, wasallowed to stand for 3 days. The reaction solution was neutralized with10% hydrochloric acid, and the precipitate was then filtered. Theresidue was washed with water and chloroform. The powder as the residuewas dried under the reduced pressure to give2-ethyl-[1,8]naphthyridin-3-ol (106 mg, yield 74%).

2-Ethyl-[1,8]naphthyridin-3-ol (30 mg), 4-chloro-6,7-dimethoxyquinoline(115 mg), and 4-dimethylaminopyridine (63 mg) were suspended ino-dichlorobenzene (2 ml), and the suspension was stirred at 140° C. for2 hr. The reaction solution was cooled to room temperature, water wasthen added to the reaction solution, and the mixture was extracted withchloroform. The chloroform layer was then washed with water andsaturated brine and was dried over anhydrous magnesium sulfate. Thesolvent was removed by distillation under the reduced pressure, and theresidue was purified by thin layer chromatography usingchloroform-methanol to give the title compound (35 mg, yield 57%).

¹H-NMR (CDCl₃, 400 MHz): δ 1.43 (t, J=7.2 Hz, 3H), 3.07 (q, J=7.2 Hz,2H), 4.02 (s, 3H), 4.05 (s, 3H), 6.45 (d, J=5.2 Hz, 1H), 7.45 (m, 1H),7.47 (s, 1H), 7.51 (s, 1H), 7.73 (s, 1H), 8.08 (dd, J=8.4, 2.0 Hz, 1H),8.52 (d, J=5.2 Hz, 1H), 9.07 (dd, J=4.4, 2.0 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 384 (M+Na)⁺

Compound 4243-(6,7-Dimethoxy-quinolin-4-yloxy)-2-ethyl-[1,6]naphthyridine

4-Aminopyridine (4.70 g) and triethylamine (6.31 g) were dissolved indichloromethane (75 ml) to prepare a solution which was then cooled to0° C. A solution of pivaloyl chloride (6.63 g) in dichloromethane (10ml) was gradually added dropwise thereto, and the mixture was stirred at0° C. for 15 min. Thereafter, the reaction solution was stirred at roomtemperature overnight. The reaction solution was poured into water (50ml). The dichloromethane layer was washed with a dilute aqueous sodiumhydrogencarbonate solution and was dried over anhydrous sodium sulfate.The solvent was removed by distillation under the reduced pressure, andthe residue was purified by column chromatography using chloroform togive 2,2-dimethyl-N-pyridin-4-yl-propionamide (7.70 g, yield 87%).

2,2-Dimethyl-N-pyridin-4-yl-propionamide (5.60 g) was dissolved intetrahydrofuran (70 ml) to prepare a solution which was cooled to −78°C. A 1.57 M n-butyllithium/n-hexane solution (62 ml) was gradually addeddropwise thereto, and the mixture was stirred at −78° C. for 15 min. Thereaction solution was stirred at 0° C. for 4 hr and was then againcooled to −78° C. A solution of N,N-dimethylformamide (6.69 g) intetrahydrofuran (7 ml) was gradually added dropwise thereto. Thetemperature was raised to room temperature. The reaction solution wasthen poured into a mixture of ice (10 g) with 6 N hydrochloric acid (30ml), and the mixture was stirred for 15 min. The aqueous layer wasneutralized with potassium carbonate powder and was extracted withdiethyl ether. The diethyl ether layer was then washed with water andsaturated brine and was dried over magnesium sulfate. The solvent wasremoved by distillation under the reduced pressure, and the residue waspurified by column chromatography using acetone-chloroform to giveN-(3-formyl-pyridin-4-yl)-2,2-dimethyl-propionamide (3.35 g, yield 52%).

N-(3-Formyl-pyridin-4-yl)-2,2-dimethyl-propionamide (3.35 g) wasdissolved in 3 N hydrochloric acid (50 ml) to prepare a solution whichwas stirred under reflux for 5.5 hr. The reaction solution was cooled toroom temperature, and the reaction solution was then washed with diethylether and was neutralized with potassium carbonate powder. Diethyl etherwas added thereto, the mixture was extracted, and the diethyl etherlayer was dried over potassium carbonate. The solvent was removed bydistillation under the reduced pressure, and the residue was purified bycolumn chromatography using acetone-chloroform to give4-amino-pyridine-3-carbaldehyde (1.12 g, yield 58%).

4-Amino-pyridine-3-carbaldehyde (100 mg) and 1-bromo-butan-2-one (124mg) were suspended in a 5 N aqueous sodium hydroxide solution (0.6 ml),and the suspension was hermetically sealed and, in this state, wasallowed to stand for 3 days. The reaction solution was neutralized with10% hydrochloric acid, the precipitate was then filtered, and theresidue was washed with water and chloroform. The powder as the residuewas dried under the reduced pressure to give2-ethyl-[1,6]naphthyridin-3-ol (69 mg, yield 48%).

2-Ethyl-[1,6]naphthyridin-3-ol (69 mg), 4-chloro-6,7-dimethoxyquinoline(265 mg), and 4-dimethylaminopyridine (145 mg) were suspended ino-dichlorobenzene (3 ml), and the mixture was stirred at 140° C. for 4hr. The reaction solution was cooled to room temperature, water was thenadded to the reaction solution, and the mixture was extracted withchloroform. The chloroform layer was then washed with water andsaturated brine and was dried over anhydrous magnesium sulfate. Thesolvent was removed by distillation under the reduced pressure, and theresidue was purified by thin layer chromatography usingchloroform-methanol to give the title compound (9 mg, yield 6%).

¹H-NMR (CDCl₃, 400 MHz): δ 1.40 (t, J=7.6 Hz, 3H), 3.06 (q, J=7.6 Hz,2H), 4.02 (s, 3H), 4.06 (s, 3H), 6.48 (d, J=5.2 Hz, 1H), 7.49 (s, 1H),7.50 (s, 1H), 7.84 (s, 1H), 7.92 (d, J=6.0 Hz, 1H), 8.54 (d, J=5.2 Hz,1H), 8.74 (d, J=6.0 Hz, 1H), 9.15 (s, 1H)

Mass spectrometric value (ESI−MS, m/z): 360 (M−1)⁻

Compound 425 3-(6,7-Dimethoxy-quinolin-4-yloxy)-naphthalen-2-ol

Naphthalene-2,3-diol (1.00 g), 4-chloro-6,7-dimethoxyquinoline (691 mg),and 4-dimethylaminopyridine (1.14 g) were suspended in o-dichlorobenzene(20 ml), and the mixture was stirred at 130° C. for one hr. The reactionsolution was cooled to room temperature, water was then added to thereaction solution, and the mixture was extracted with chloroform. Thechloroform layer was then washed with water and saturated brine and wasdried over anhydrous magnesium sulfate. The solvent was removed bydistillation under the reduced pressure, and the residue was purified bycolumn chromatography using chloroform-methanol to give the titlecompound (627 mg, yield 58%).

¹H-NMR (CD₃OD, 400 MHz): δ 4.02 (s, 6H), 6.46 (d, J=5.2 Hz, 1H),7.28-7.37 (m, 3H), 7.41 (m, 1H), 7.63 (s, 1H), 7.73 (m, 3H), 8.37 (d,J=5.2 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 346 (M−1)⁻

Compound 4262-Tert-butyl-3-(6,7-dimethoxy-quinolin-4-yloxy)-[1,8]naphthyridine

2-Amino-pyridine-3-carbaldehyde (100 mg) and1-bromo-3,3-dimethyl-butan-2-one (147 mg) were suspended in a 5 Naqueous sodium hydroxide solution (0.6 ml), and the suspension washermetically sealed and, in this state, was allowed to stand for 3 days.The reaction solution was neutralized with 10% hydrochloric acid, andthe resultant precipitate was then collected by filtration and waswashed with water and chloroform. The powder as the residue was driedunder the reduced pressure to give 2-tert-butyl-[1,8]naphthyridin-3-ol(40 mg, yield 24%).

2-Tert-butyl-[1,8]naphthyridin-3-ol (40 mg),4-chloro-6,7-dimethoxyquinoline (132 mg), and 4-dimethylaminopyridine(72 mg) were suspended in o-dichlorobenzene (3 ml), and the suspensionwas stirred at 140° C. for 5.5 hr. The reaction solution was cooled toroom temperature, water was then added to the reaction solution, and themixture was extracted with chloroform. The chloroform layer was thenwashed with water and saturated brine and was dried over anhydrousmagnesium sulfate. The solvent was removed by distillation under thereduced pressure, and the residue was purified by column chromatographyusing chloroform-methanol to give the title compound (7 mg, yield 9%).

¹H-NMR (CDCl₃, 400 MHz): δ 1.61 (s, 9H), 3.99 (s, 3H), 4.06 (s, 3H),6.64 (d, J=5.2 Hz, 1H), 7.44 (dd, J=8.4, 4.4 Hz, 1H), 7.49 (s, 1H), 7.52(s, 1H), 7.64 (s, 1H), 8.01 (dd, J=8.4, 2.0 Hz, 1H), 8.58 (d, J=5.2 Hz,1H), 9.07 (dd, J=4.4, 2.0 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 412 (M+Na)⁺

Compound 427 3-(6,7-Dimethoxy-quinolin-4-yloxy)-[1,8]naphthyridine

2-Amino-pyridine-3-carbaldehyde (100 mg),3-bromo-1,1,1-trifluoro-propan-2-one (157 mg) were suspended in a 5 Naqueous sodium hydroxide solution (0.6 ml), and the suspension washermetically sealed and, in this state, was allowed to stand for 3 days.The reaction solution was neutralized with 10% hydrochloric acid, andthe resultant precipitate was then collected by filtration and waswashed with water and chloroform. The powder as the residue was driedunder the reduced pressure to give3-hydroxy-[1,8]naphthyridine-2-carboxylic acid (16 mg, yield 9%).

3-Hydroxy-[1,8]naphthyridine-2-carboxylic acid (15 mg),4-chloro-6,7-dimethoxyquinoline (47 mg), and 4-dimethylaminopyridine (26mg) were suspended in o-dichlorobenzene (1 ml), and the suspension wasstirred at 140° C. for 24 hr. The reaction solution was cooled to roomtemperature, water was then added to the reaction solution, and themixture was extracted with chloroform. The chloroform layer was thenwashed with water and saturated brine and was dried over anhydrousmagnesium sulfate. The solvent was removed by distillation under thereduced pressure, and the residue was purified by column chromatographyusing chloroform-methanol to give the title compound (6 mg, yield 26%).

¹H-NMR (CDCl₃, 400 MHz): δ 4.02 (s, 3H), 4.05 (s, 3H), 6.59 (d, J=5.2Hz, 1H), 7.48-7.58 (m, 3H), 7.85 (d, J=3.2 Hz, 1H), 8.15 (dd, J=8.4, 2.0Hz, 1H), 8.55 (d, J=5.2 Hz, 1H), 9.10 (d, J=3.2 Hz, 1H), 9.13 (dd,J=4.0, 2.0 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 356 (M+Na)⁺

Compound 4283-(6,7-Dimethoxy-quinolin-4-yloxy)-2-p-tolyl-[1,8]naphthyridine

2-Amino-pyridine-3-carbaldehyde (100 mg) and 2-bromo-1-p-tolyl-ethanone(174 mg) were suspended in a 5 N aqueous sodium hydroxide solution (0.6ml), and the suspension was hermetically sealed and, in this state, wasallowed to stand for 3 days. The reaction solution was neutralized with10% hydrochloric acid, and the resultant precipitate was then collectedby filtration and was washed with water and chloroform. The powder asthe residue was dried under the reduced pressure to give2-p-toluoyl-[1,8]naphthyridin-3-ol (2 mg, yield 1%).

2-p-Toluyl-[1,8]naphthyridin-3-ol (2 mg),4-chloro-6,7-dimethoxyquinoline (6 mg), and 4-dimethylaminopyridine (3mg) were suspended in o-dichlorobenzene (1 ml), and the suspension wasstirred at 130° C. for 14.5 hr. The reaction solution was cooled to roomtemperature, water was then added to the reaction solution, and themixture was extracted with chloroform. The chloroform layer was thenwashed with water and saturated brine and was dried over anhydrousmagnesium sulfate. The solvent was removed by distillation under thereduced pressure, and the residue was purified by column chromatographyusing chloroform-methanol to give the title compound (0.7 mg, yield20%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.28 (s, 3H), 4.11 (s, 3H), 4.12 (s, 3H),6.47 (d, J=5.2 Hz, 1H), 7.10 (m, 2H), 7.50 (s, 1H), 7.58 (m, 1H), 7.62(s, 1H), 7.29 (m, 2H), 8.08 (s, 1H), 8.23 (m, 1H), 8.35 (d, J=5.2 Hz,1H), 9.20 (m, 1H)

Mass spectrometric value (ESI−MS, m/z): 446 (M+Na)⁺

Compound 4293-(6,7-Dimethoxy-quinolin-4-yloxy)-5,6,3′-trimethyl-[2,2′]bipyridine

2-Bromo-3-methylpyridine (1.53 g) was dissolved in tetrahydrofuran (40ml) under an argon atmosphere to prepare a solution. A 1.6Mn-butyllithium/n-hexane solution (5.7 ml) was added dropwise to thesolution at −78° C., and the mixture was then stirred at −78° C. for 30min. A solution of 4,5-dimethylfurfural (1.00 g) in tetrahydrofuran (20ml) was added dropwise thereto, and the temperature of the mixture wasraised to room temperature while stirring. Water was added to thereaction solution to stop the reaction. The solvent was removed bydistillation under the reduced pressure, water was added to the residue,and the mixture was extracted with ethyl acetate. The ethyl acetatelayer was then washed with water and was dried over anhydrous sodiumsulfate. The solvent was removed by distillation under the reducedpressure, and the residue was purified by column chromatography usinghexane-ethyl acetate to give(4,5-dimethylfuran-2-yl)-(3-methylpyridin-2-yl)-methanol (1.17 g, yield61%).

(4,5-Dimethylfuran-2-yl)-(3-methylpyridin-2-yl)-methanol (1.17 g) wasdissolved in chloroform (30 ml) to prepare a solution. Manganese dioxide(4.69 g) was added to the solution, and the mixture was stirred at roomtemperature overnight. The reaction solution was filtered throughCelite, and the solvent was removed from the filtrate by distillationunder the reduced pressure to give(4,5-dimethylfuran-2-yl)-(3-methylpyridin-2-yl)-methanone (940 mg, yield81%).

(4,5-Dimethylfuran-2-yl)-(3-methylpyridin-2-yl)-methanone (930 mg),methanol (7.5 ml), and a 28% aqueous ammonia solution (9 ml) were placedin a sealed tube and was stirred at 160° C. overnight. The reactionsolution was cooled to room temperature, and the solvent was thenremoved by distillation under the reduced pressure, and the residue waspurified by column chromatography using hexane-ethyl acetate to give5,6,3′-trimethyl-[2,2′]bipyridin-3-ol (109 mg, yield 86%).

Dimethyl sulfoxide (1.4 ml) was added to5,6,3′-trimethyl-[2,2′]bipyridin-3-ol (30 mg),4-chloro-6,7-dimethoxyquinoline (94 mg), cesium carbonate (137 mg), and4-(N,N-dimethylamino)-pyridine (51 mg), and the mixture was stirred at140° C. overnight. The reaction solution was cooled to room temperature,water was then added to the reaction solution, and the mixture wasextracted with ethyl acetate. The ethyl acetate layer was washed withwater and was dried over anhydrous sodium sulfate. The solvent wasremoved by distillation under the reduced pressure, and the residue waspurified by thin layer chromatography using hexane-acetone to give thetitle compound (29 mg, yield 52%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.30 (s, 3H), 2.39 (s, 3H), 2.62 (s, 3H),3.99 (s, 3H), 4.00 (s, 3H), 6.46 (d, J=5.4 Hz, 1H), 7.01 (dd, J=4.6, 7.8Hz, 1H), 7.33 (s, 1H), 7.36-7.42 (m, 3H), 8.31-8.37 (m, 1H), 8.40 (d,J=5.4 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 424 (M+Na)⁺

Compound 4303-(6,7-Methoxyquinolin-4-yloxy)-6′-hydroxy-5,6-dimethyl-[2,3′]bipyridine

3-Bromo-6-methoxypyridine (1.67 g) was dissolved in tetrahydrofuran (40ml) under an argon atmosphere to prepare a solution. A 1.6 Mn-butyllithium/hexane solution (5.7 ml) was added dropwise to thesolution at −78° C., and the mixture was then stirred at −78° C. for 30min. A solution of 4,5-dimethylfurfural (1.00 g) in tetrahydrofuran (20ml) was added dropwise thereto, and the temperature of the mixture wasraised to room temperature while stirring. Water was added to thereaction solution to stop the reaction, and the solvent was removed bydistillation under the reduced pressure. Water was added to the residue,and the mixture was extracted with ethyl acetate. The ethyl acetatelayer was then washed with water and was dried over anhydrous sodiumsulfate. The solvent was removed by distillation under the reducedpressure, and the residue was purified by column chromatography usinghexane-ethyl acetate to give(4,5-dimethylfuran-2-yl)-(6-methoxypyridin-3-yl)-methanol (1.24 g, yield60%).

(4,5-Dimethylfuran-2-yl)-(6-methoxypyridin-3-yl)-methanol (1.24 g) wasdissolved in chloroform (30 ml) to prepare a solution. Manganese dioxide(4.63 g) was added to the solution, and the mixture was stirred at roomtemperature overnight. Manganese dioxide (4.63 g) was then added to thereaction solution, and the mixture was stirred for 6 hr. The reactionsolution was filtered through Celite, and the solvent was removed fromthe filtrate by distillation under the reduced pressure to give(4,5-dimethylfuran-2-yl)-(6-methoxypyridin-3-yl)-methanone (655 mg,yield 53%).

(4,5-Dimethylfuran-2-yl)-(6-methoxypyridin-3-yl)-methanone (650 mg),methanol (6 ml), and a 28% aqueous ammonia solution (6 ml) were placedin a sealed tube and was stirred at 160° C. overnight. The reactionsolution was cooled to room temperature, the solvent was then removed bydistillation under the reduced pressure, and the residue was purified bycolumn chromatography using hexane-ethyl acetate to give6′-methoxy-5,6-dimethyl-[2,3′]bipyridin-3-ol (109 mg, yield 86%).

1,2-Dichlorobenzene (1.3 ml) was added to6′-methoxy-5,6-dimethyl-[2,3′]bipyridin-3-ol (30 mg),4-chloro-6,7-dimethoxyquinoline (88 mg), and4-(N,N-dimethylamino)-pyridine (48 mg), and the mixture was stirred at140° C. overnight. The reaction solution was cooled to room temperature,water was then added to the reaction solution, and the mixture wasextracted with ethyl acetate. The ethyl acetate layer was washed withwater and was dried over anhydrous sodium sulfate. The solvent wasremoved by distillation under the reduced pressure, and the residue waspurified by thin layer chromatography using chloroform-methanol to givethe title compound (12 mg, yield 23%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.30 (s, 3H), 2.56 (s, 3H), 4.03 (s, 3H),4.04 (s, 3H), 6.37 (d, J=5.4 Hz, 1H), 6.49 (d, J=9.5 Hz, 1H), 7.19 (s,1H), 7.42 (s, 1H), 7.46 (s, 1H), 8.10-8.20 (m, 2H), 8.46 (d, J=5.1 Hz,1H)

Mass spectrometric value (ESI−MS, m/z): 402 (M−1)⁻

Compound 431 5,6,5′-Trimethyl-3-(quinolin-4-yloxy)-[2,2′]-bipyridine

Dimethyl sulfoxide (2 ml) was added to5,6,5′-trimethyl-[2,2′]bipyridin-3-ol (50 mg), 4-chloroquinoline (115mg), and cesium carbonate (228 mg), and the mixture was stirred at 140°C. for 5 hr. The reaction solution was cooled to room temperature, waterwas then added to the reaction solution, and the mixture was extractedwith ethyl acetate. The ethyl acetate layer was washed with water andwas dried over anhydrous sodium sulfate. The solvent was removed bydistillation under the reduced pressure, and the residue was purified bythin layer chromatography using chloroform-methanol to give the titlecompound (57 mg, yield 72%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.22 (s, 3H), 2.38 (s, 3H), 2.66 (s, 3H),6.42 (d, J=5.1 Hz, 1H), 7.34-7.39 (m, 2H), 7.54-7.60 (m, 1H), 7.72 (d,J=7.8 Hz, 1H), 7.74 (ddd, J=8.6, 7.1, 1.5 Hz, 1H), 8.05 (d, J=8.5 Hz,1H), 8.32-8.39 (m, 2H), 8.56 (d, J=5.4 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 342 (M+1)⁺

Compound 4323-(7-Chloroquinolin-4-yloxy)-5,6,5′-trimethyl-[2,2′]-bipyridine

Dimethyl sulfoxide (2 ml) was added to5,6,5′-trimethyl-[2,2′]bipyridin-3-ol (50 mg), 4,7-dichloroquinoline(139 mg), and cesium carbonate (228 mg), and the mixture was stirred at140° C. for 5 hr. The reaction solution was cooled to room temperature,water was then added to the reaction solution, and the mixture wasextracted with ethyl acetate. The ethyl acetate layer was washed withwater and was dried over anhydrous sodium sulfate. The solvent wasremoved by distillation under the reduced pressure, and the residue waspurified by thin layer chromatography using chloroform-methanol to givethe title compound (77 mg, yield 94%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.22 (s, 3H), 2.39 (s, 3H), 2.65 (s, 3H),6.39 (d, J=5.4 Hz, 1H), 7.34-7.40 (m, 2H), 7.52 (dd, J=2.0, 8.8 Hz, 1H),7.72 (d, J=8.0 Hz, 1H), 8.04 (d, J=2.2 Hz, 1H), 8.26-8.29 (m, 1H), 8.30(d, J=9.0 Hz, 1H), 8.54 (d, J=5.4 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 398 (M+Na)⁺

Compound 4335,6,5′-Trimethyl-3-(7-trifluoromethylquinolin-4-yloxy)-[2,2′]-bipyridine

Dimethyl sulfoxide (2 ml) was added to5,6,5′-trimethyl-[2,2′]bipyridin-3-ol (50 mg),4-chloro-7-trifluoromethylquinoline (162 mg), and cesium carbonate (228mg), and the mixture was stirred at 140° C. for 5 hr. The reactionsolution was cooled to room temperature, water was then added to thereaction solution, and the mixture was extracted with ethyl acetate. Theethyl acetate layer was washed with water and was dried over anhydroussodium sulfate. The solvent was removed by distillation under thereduced pressure, and the residue was purified by thin layerchromatography using hexane-acetone to give the title compound (72 mg,yield 75%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.21 (s, 3H), 2.39 (s, 3H), 2.65 (s, 3H),6.50 (d, J=5.4 Hz, 1H), 7.36-7.42 (m, 2H), 7.72-7.79 (m, 2H), 8.22-8.27(m, 1H), 8.35 (s, 1H), 8.50 (d, J=8.8 Hz, 1H), 8.64 (d, J=5.1 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 432 (M+Na)⁺

Compound 4346,7-Dimethoxy-4-[6-methyl-2-(1H-pyrazol-4-yl)-pyridin-3-yloxy]-quinoline

N,N-Dimethylformamide (1.2 ml) and a 2 M aqueous potassium carbonatesolution (1 ml) were added to4-[(2-iodo-6-methyl-3-pyridyl)oxy]-6,7-dimethoxy-quinoline (compound116) (50 mg), tetrakistriphenylphosphine palladium (70 mg), and4-(4,4,5,5-tetramethyl-[1,3]dioxolan-2-ylboranyl)-1H-pyrazole (34 mg)under an argon atmosphere, and the mixture was stirred at 70° C. for 4hr. The reaction solution was cooled to room temperature and was thenfiltered through Celite. The solvent was removed from the filtrate bydistillation under the reduced pressure. Water was added to the residue,and the mixture was extracted with ethyl acetate. The ethyl acetatelayer was then washed with water. The ethyl acetate layer was extractedwith 1 N hydrochloric acid. The aqueous layer was then made alkaline bythe addition of a 1 N aqueous sodium hydroxide solution and wasextracted with ethyl acetate. The ethyl acetate layer was washed withwater and was dried over anhydrous sodium sulfate. The solvent wasremoved by distillation under the reduced pressure, and the residue waspurified by thin layer chromatography using hexane-acetone to give thetitle compound (19 mg, yield 44%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.64 (s, 3H), 4.04 (s, 6H), 6.36 (d, J=5.4Hz, 1H), 7.10 (d, J=8.3 Hz, 1H), 7.37 (d, J=8.3 Hz, 1H), 7.45 (s, 1H),7.62 (s, 1H), 8.13 (s, 2H), 8.44 (d, J=5.4 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 363 (M+1)⁺

Compound 4353-(6,7-Methoxyquinolin-4-yloxy)-5,6,4′-trimethyl-[2,3′]bipyridine

3-Bromo-4-methylpyridine (500 mg) was dissolved in tetrahydrofuran (15ml) under an argon atmosphere to prepare a solution. A 1.6 Mn-butyllithium/hexane solution (2 ml) was added dropwise to the solutionat −78° C., and the mixture was then stirred at −78° C. for 30 min. Asolution of 4,5-dimethylfurfural (350 mg) in tetrahydrofuran (2 ml) wasadded dropwise thereto, and the temperature of the reaction solution wasraised to room temperature while stirring. Water was added to thereaction solution to stop the reaction, and the solvent was removed bydistillation under the reduced pressure. Water was added to the residue,and the mixture was extracted with ethyl acetate. The ethyl acetatelayer was then washed with water and was dried over anhydrous sodiumsulfate. The solvent was removed by distillation under the reducedpressure, and the residue was purified by column chromatography usinghexane-ethyl acetate to give(4,5-dimethylfuran-2-yl)-(4-methylpyridin-3-yl)-methanol (174 mg, yield28%).

(4,5-Dimethylfuran-2-yl)-(4-methylpyridin-3-yl)-methanol (174 mg) wasdissolved in chloroform (5 ml) to prepare a solution. Manganese dioxide(1.05 g) was added to the solution, and the mixture was stirred at roomtemperature overnight. The reaction solution was then filtered throughCelite. The solvent was removed from the filtrate by distillation underthe reduced pressure. The residue was purified by column chromatographyusing hexane-ethyl acetate to give(4,5-dimethylfuran-2-yl)-(4-methylpyridin-3-yl)-methanone (151 mg, yield88%).

(4,5-Dimethylfuran-2-yl)-(4-methylpyridin-3-yl)-methanone (150 mg),methanol (2 ml), and a 28% aqueous ammonia solution (2 ml) were placedin a sealed tube and was stirred at 160° C. overnight. The reactionsolution was cooled to room temperature, and the solvent was thenremoved by distillation under the reduced pressure, and the residue waspurified by thin layer chromatography using hexane-acetone to give5,6,4′-trimethyl-[2,3′]bipyridin-3-ol (30 mg, yield 20%).

1,2-Dichlorobenzene (1.3 ml) was added to5,6,4′-trimethyl-[2,3′]bipyridin-3-ol (27 mg),4-chloro-6,7-dimethoxyquinoline (85 mg), and4-(N,N-dimethylamino)-pyridine (46 mg), and the mixture was stirred at130° C. overnight. The reaction solution was cooled to room temperature,and the solvent was then removed by distillation under the reducedpressure. The residue was purified by thin layer chromatography usingchloroform-methanol to give the title compound (44 mg, yield 87%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.31 (s, 3H), 2.40 (s, 3H), 2.61 (s, 3H),3.99 (s, 3H), 4.00 (s, 3H), 6.36 (d, J=5.1 Hz, 1H), 7.04 (d, J=5.1 Hz,1H), 7.30 (s, 1H), 7.34 (s, 1H), 7.39 (s, 1H), 8.30 (d, J=5.1 Hz, 1H),8.42 (d, J=5.4 Hz, 1H), 8.33 (s, 1H)

Mass spectrometric value (ESI−MS, m/z): 402 (M+1)⁺

Compound 4366,7-Dimethoxy-4-(2-phenyl-[1,8]naphthyridin-3-yloxy-quinazoline

1,2-Dichlorobenzene (1 ml) was added to 2-phenyl-[1,8]naphthyridin-3-ol(10 mg), 4-chloro-6,7-dimethoxyquinazoline (30 mg), and4-(N,N-dimethylamino)-pyridine (17 mg), and the mixture was stirred at120° C. overnight. The reaction solution was cooled to room temperature,water was then added to the reaction solution, and the mixture wasextracted with chloroform. The chloroform layer was washed with waterand was dried over anhydrous sodium sulfate. The solvent was removed bydistillation under the reduced pressure, and the residue was purified bythin layer chromatography using hexane-acetone to give the titlecompound (18 mg, yield 97%).

¹H-NMR (CDCl₃, 400 MHz): δ 4.04 (s, 3H), 4.06 (s, 3H), 7.30-7.34 (m,4H), 7.46 (s, 1H), 7.54 (dd, J=4.2, 8.0 Hz, 1H), 7.97-8.03 (m, 2H), 8.26(dd, J=2.0, 8.3 Hz, 1H), 8.32 (s, 1H), 8.52 (s, 1H), 9.17 (dd, J=2.0,4.2 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 433 (M+Na)⁺

Compound 4376,7-Dimethoxy-4-(5,6,5′-trimethyl-[2,2′]bipyridin-3-yloxy)-quinazoline

Dimethyl sulfoxide (1.4 ml) was added to5,6,5′-trimethyl-[2,2′]bipyridin-3-ol (30 mg),4-chloro-6,7-dimethoxyquinazoline (94 mg), and cesium carbonate (137mg), and the mixture was stirred at 130° C. for 4 hr. The reactionsolution was cooled to room temperature, water was then added to thereaction solution, the mixture was filtered, and the residue was washedwith chloroform/methanol. The solvent was removed from the filtrate bydistillation under the reduced pressure, water was added to the residue,and the mixture was extracted with chloroform. The chloroform layer waswashed with water and was then dried over anhydrous sodium sulfate. Thesolvent was removed by distillation under the reduced pressure, and theresidue was purified by thin layer chromatography using hexane-acetoneto give the title compound (51 mg, yield 91%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.20 (s, 3H), 2.39 (s, 3H), 2.62 (s, 3H),4.04 (s, 3H), 4.05 (s, 3H), 7.27-7.30 (m, 1H), 7.40-7.45 (m, 1H), 7.47(s, 1H), 7.57 (s, 1H), 7.80 (d, J=8.0 Hz, 1H), 8.08-8.12 (m, 1H), 8.48(s, 1H)

Mass spectrometric value (ESI−MS, m/z): 425 (M+Na)⁺

Compound 4386,7-Dimethoxy-4-[6-methyl-2-(1-methyl-1H-pyrazol-4-yl)-pyridin-3-yloxy]-quinoline

6,7-Dimethoxy-4-[6-methyl-2-(1H-pyrazol-4-yl)-pyridin-3-yloxy]-quinoline(compound 434) (30 mg) was suspended in N,N-dimethylformamide (1 ml),60% sodium hydride (9.9 mg) was added to the suspension, and the mixturewas then stirred for 30 min. Methyl iodide (18 mg) was added to thereaction solution, and the mixture was stirred for one hr. Water wasadded to the reaction solution to stop the reaction, and the mixture wasextracted with ethyl acetate. The ethyl acetate layer was washed withwater and was then dried over anhydrous sodium sulfate. The solvent wasremoved by distillation under the reduced pressure. The residue waspurified by thin layer chromatography using hexane-acetone to give thetitle compound (23 mg, yield 73%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.63 (s, 3H), 3.82 (s, 3H), 4.06 (s, 3H),4.07 (s, 3H), 6.37 (d, J=5.4 Hz, 1H), 7.07 (d, J=8.3 Hz, 1H), 7.34 (d,J=8.3 Hz, 1H), 7.46 (s, 1H), 7.63 (s, 1H), 7.91 (s, 1H), 8.02 (s, 1H),8.45 (d, J=5.1 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 377 (M+1)⁺

Compound 4396,7-Dimethoxy-4-[2-(3-methyl-butyl)-quinolin-3-yloxy]-quinoline

4-[2-(5-Chloro-4-methyl-thiophen-2-yl)-quinolin-3-yloxy]-6,7-dimethoxy-quinoline(compound 290) (7 mg) was dissolved intriethylamine/N,N-dimethylformamide (0.5 ml/1.5 ml) to prepare asolution, 20% palladium hydroxide (68 mg) was added to the solution, andthe mixture was stirred under a hydrogen gas atmosphere at roomtemperature overnight. The reaction solution was filtered, and thesolvent was then removed by distillation under the reduced pressure.Water was added to the residue, and the mixture was extracted with ethylacetate. The ethyl acetate layer was then washed with water and wasdried over anhydrous sodium sulfate. The solvent was removed bydistillation under the reduced pressure, and the residue was purified bythin layer chromatography using acetone-chloroform to give the titlecompound (3.6 mg, yield 56%).

¹H-NMR (CDCl₃, 400 MHz): δ 0.85 (d, J=6.6 Hz, 6H), 1.46-1.84 (m, 3H),2.96 (m, 2H), 4.06 (s, 3H), 4.08 (s, 3H), 6.45 (d, J=5.4 Hz, 1H), 7.48(s, 1H), 7.53 (m, 1H), 7.59 (s, 1H), 7.69-7.75 (m, 2H), 7.79 (s, 1H),8.12 (d, J=8.6 Hz, 1H), 8.52 (d, J=5.1 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 403 (M+1)⁺

Compound 4403-[6-Methoxy-7-(2-piperidin-1-yl-ethoxy)-quinolin-4-yloxy]-2-methyl-[1,8]naphthyridine

3-[7-Hydroxy-6-methoxy-quinolin-4-yloxy]-2-methyl-[1,8]naphthyridine (67mg) was dissolved in N,N-dimethylformamide (5 ml) to prepare a solution.Potassium carbonate (225 mg) and 1-bromo-2-chloroethane (0.15 ml) wereadded to the solution, and the mixture was stirred at room temperatureovernight. Potassium carbonate (300 mg) and piperidine (0.5 ml) wereadded to the reaction solution, and the mixture was further stirred at70° C. overnight. The reaction solution was cooled to room temperature,water was then added to the reaction solution, and the mixture wasextracted with chloroform. The chloroform layer was washed withsaturated brine and was dried over anhydrous sodium sulfate. The solventwas removed by distillation under the reduced pressure, and the residuewas purified by thin layer chromatography using chloroform-methanol togive the title compound (69 mg, yield 78%) (2 steps).

¹H-NMR (CDCl₃, 400 MHz): δ 1.49 (m, 2H), 1.62-1.68 (m, 4H), 2.59 (m,4H), 2.77 (s, 3H), 2.95 (t, J=6.1 Hz, 2H), 4.03 (s, 3H), 4.36 (t, J=6.1Hz, 2H), 6.44 (d, J=5.1 Hz, 1H), 7.48 (s, 1H), 7.49 (m, 1H), 7.52 (s,1H), 7.77 (s, 1H), 8.11 (dd, J=1.9 Hz, 8.0 Hz, 1H), 8.54 (d, J=5.1 Hz,1H), 9.10 (dd, J=1.9 Hz, 4.2 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 467 (M+Na)⁺

Compound 4413-[6-Methoxy-7-(2-morpholin-4-yl-ethoxy)-quinolin-4-yloxy]-2-methyl-[1,8]naphthyridine

3-[7-Hydroxy-6-methoxy-quinolin-4-yloxy]-2-methyl-[1,8]naphthyridine (67mg) was dissolved in N,N-dimethylformamide (5 ml) to prepare a solution.Potassium carbonate (225 mg) and 1-bromo-2-chloroethane (0.15 ml) wereadded to the solution, and the mixture was stirred at room temperatureovernight. Morpholine (0.3 ml) was added to the reaction solution, andthe mixture was further stirred overnight at 70° C. Potassium carbonate(354 mg) and morpholine (0.2 ml) were further added to the reactionsolution, and the mixture was stirred at 70° C. overnight. The reactionsolution was cooled to room temperature, water was then added to thereaction solution, and the mixture was extracted with chloroform. Thechloroform layer was washed with saturated brine and was dried overanhydrous sodium sulfate. The solvent was removed by distillation underthe reduced pressure, and the residue was purified by thin layerchromatography using chloroform-methanol to give the title compound (11mg, yield 12%) (2 steps).

¹H-NMR (CDCl₃, 400 MHz): δ 2.65 (m, 4H), 2.76 (s, 3H), 2.97 (t, J=5.9Hz, 2H), 3.76 (m, 4H), 4.03 (s, 3H), 4.36 (t, J=6.1 Hz, 2H), 6.44 (d,J=5.2 Hz, 1H), 7.48 (s, 1H), 7.49 (m, 1H), 7.53 (s, 1H), 7.77 (s, 1H),8.11 (dd, J=1.7 Hz, 8.1 Hz, 1H), 8.54 (d, J=5.1 Hz, 1H), 9.11 (dd, J=2.0Hz, 4.4 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 469 (M+Na)⁺

Compound 4423-(7-Benzyloxy-6-methoxy-quinolin-4-yloxy)-5,6,6′-trimethyl-[2,2′]bipyridine

5,6,6′-Trimethyl-[2,2′]bipyridin-3-ol (300 mg),7-benzyloxy-4-chloro-6-methoxyquinoline (1.26 g),4-dimethylaminopyridine (513 mg), and cesium carbonate (1.37 g) weresuspended in dimethyl sulfoxide (6 ml), and the suspension was stirredat 130° C. overnight. The reaction solution was cooled to roomtemperature, water was then added to the reaction solution, and themixture was extracted with chloroform. The chloroform layer was washedwith saturated brine and was dried over anhydrous sodium sulfate. Thesolvent was removed by distillation under the reduced pressure, and theresidue was purified by column chromatography using chloroform-methanolto give the title compound (483 mg, yield 72%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.19 (s, 3H), 2.38 (s, 3H), 2.64 (s, 3H),4.03 (s, 3H), 5.31 (s, 2H), 6.31 (d, J=5.4 Hz, 1H), 6.93 (d, J=7.3 Hz,1H), 7.30-7.65 (m, 10H), 8.33 (d, J=5.4 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 478 (M+1)⁺

Compound 4436-Methoxy-4-(5,6,6′-trimethyl-[2,2′]bipyridin-3-yloxy)-quinolin-7-ol

3-(7-Benzyloxy-6-methoxy-quinolin-4-yloxy)-5,6,6′-trimethyl-[2,2′]bipyridine(compound 442) (475 mg) was dissolved in trifluoroacetic acid (4.7 ml)to prepare a solution. Methanesulfonic acid (0.47 ml) was added to thesolution, and the mixture was stirred at 70° C. for one hr. The reactionsolution was cooled to room temperature, and the solvent was removed bydistillation under the reduced pressure. An aqueous sodiumhydrogencarbonate solution was then added to the residue, and themixture was extracted with chloroform. The chloroform layer was washedwith saturated brine and was dried over anhydrous sodium sulfate. Thesolvent was removed by distillation under the reduced pressure, and theresidue was purified by column chromatography using chloroform-methanolto give the title compound (433 mg, yield 100%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.17 (s, 3H), 2.39 (s, 3H), 2.64 (s, 3H),4.06 (s, 3H), 6.31 (d, J=5.4 Hz, 1H), 6.93 (d, J=7.6 Hz, 1H), 7.38 (s,1H), 7.47-7.66 (m, 4H), 8.36 (d, J=5.4 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 388 (M+1)⁺

Compound 4444-[4-(5,6-Dimethyl-[2,3′]bipyridin-3-yloxy)-6-methoxy-quinolin-7-yloxy]-butan-1-ol

4-(5,6-Dimethyl-[2,3′]bipyridin-3-yloxy)-6-methoxy-quinolin-7-ol(compound 345) (45 mg) was dissolved in N,N-dimethylformamide (2 ml) toprepare a solution. Potassium carbonate (50 mg) and 4-bromo-1-butanol(55 mg) were added to the solution, and the mixture was stirred at roomtemperature overnight. Water was added to the reaction solution, themixture was extracted with ethyl acetate, and the ethyl acetate layerwas then washed with saturated brine and was dried over anhydrous sodiumsulfate. The solvent was removed by distillation under the reducedpressure, and the residue was purified by thin layer chromatographyusing chloroform-acetone to give the title compound (19 mg, yield 35%).

¹H-NMR (CDCl₃, 400 MHz): δ 1.79-1.85 (m, 2H), 2.03-2.09 (m, 2H), 2.37(s, 3H), 2.63 (s, 3H), 3.77 (t, J=6.1 Hz, 2H), 4.01 (s, 3H), 4.25 (t,J=6.3 Hz, 2H), 6.37 (d, J=5.1 Hz, 1H), 7.21-7.25 (m, 1H), 7.31 (s, 1H),7.44 (s, 1H), 7.46-7.48 (m, 1H), 8.16 (d, J=7.8 Hz, 1H), 8.43 (d, J=5.4Hz, 1H), 8.49 (d, J=4.9 Hz, 1H), 9.13-9.14 (m, 1H)

Mass spectrometric value (ESI−MS, m/z): 446 (M+1)⁺

Compound 4454-[4-(5,6-Dimethyl-[2,2′]bipyridin-3-yloxy)-6-methoxy-quinolin-7-yloxy]-butan-1-ol

4-(5,6-Dimethyl-[2,2′]bipyridin-3-yloxy)-6-methoxy-quinolin-7-ol(compound 338) (45 mg) was suspended in N,N-dimethylformamide (4 ml).Potassium carbonate (50 mg) and 4-bromo-1-butanol (55 mg) were added tothe suspension, and the mixture was stirred at room temperatureovernight. Water was added to the reaction solution, and the mixture wasextracted with ethyl acetate. The ethyl acetate layer was then washedwith saturated brine and was dried over anhydrous sodium sulfate. Thesolvent was removed by distillation under the reduced pressure, and theresidue was purified by thin layer chromatography usingchloroform-acetone to give the title compound (26 mg, yield 48%).

¹H-NMR (CDCl₃, 400 MHz): δ 1.78-1.85 (m, 2H), 2.03-2.09 (m, 2H), 2.39(s, 3H), 2.66 (s, 3H), 3.77 (t, J=6.1 Hz, 2H), 4.01 (s, 3H), 4.25 (t,J=6.3 Hz, 2H), 6.38 (d, J=5.4 Hz, 1H), 7.10-7.13 (m, 1H), 7.37 (s, 1H),7.42-7.61 (m, 3H), 7.79-7.83 (m, 1H), 8.38 (d, J=5.4 Hz, 1H), 8.48-8.51(m, 1H)

Mass spectrometric value (ESI−MS, m/z): 446 (M+1)⁺

Compound 4463-(6-Methoxy-7-oxiranylmethoxy-quinolin-4-yloxy)-5,6,6′-trimethyl-[2,2′]bipyridine

6-Methoxy-4-(5,6,6′-trimethyl-[2,2′]bipyridin-3-yloxy)-quinolin-7-ol(compound 443) (87 mg) was dissolved in N,N-dimethylformamide (4 ml) toprepare a solution, and potassium carbonate (93 mg) and epibromohydrin(0.06 ml) were added to the solution. The mixture was stirred at roomtemperature overnight. Water was added to the reaction solution, and themixture was extracted with ethyl acetate. The ethyl acetate layer wasthen washed with saturated brine and was dried over anhydrous sodiumsulfate. The solvent was removed by distillation under the reducedpressure, and the residue was purified by thin layer chromatographyusing chloroform-methanol to give the title compound (97 mg, yield 99%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.17 (s, 3H), 2.39 (s, 3H), 2.64 (s, 3H),2.83-2.85 (m, 1H), 2.95-2.97 (m, 1H), 3.49-3.53 (m, 1H), 4.02 (s, 3H),4.14-4.20 (m, 1H), 4.43 (dd, J=3.4 Hz, 11.5 Hz, 1H), 6.32 (d, J=5.4 Hz,1H), 6.93 (d, J=7.8 Hz, 1H), 7.38-7.67 (m, 5H), 8.35 (d, J=5.4 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 444 (M+1)⁺

Compound 4473-[6-Methoxy-4-(5,6,6′-trimethyl-[2,2′]bipyridin-3-yloxy)-quinolin-7-yloxy]-propan-1-ol

6-Methoxy-4-(5,6,6′-trimethyl-[2,2′]bipyridin-3-yloxy)-quinolin-7-ol(compound 443) (50 mg) was dissolved in N,N-dimethylformamide (2 ml) toprepare a solution. Potassium carbonate (54 mg) and 3-bromo-1-propanol(0.03 ml) were added to the solution, and the mixture was stirred atroom temperature overnight. The solvent was removed by distillationunder the reduced pressure. Water was then added to the residue, and themixture was extracted with chloroform. The chloroform layer was washedwith saturated brine and was dried over anhydrous sodium sulfate. Thesolvent was removed by distillation under the reduced pressure, and theresidue was purified by thin layer chromatography usingchloroform-acetone to give the title compound (36 mg, yield 62%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.16-2.22 (m, 2H), 2.18 (s, 3H), 2.39 (s,3H), 2.64 (s, 3H), 3.92-3.94 (m, 2H), 4.00 (s, 3H), 4.37 (t, J=6.1 Hz,2H), 6.33 (d, J=5.4 Hz, 1H), 6.93 (d, J=7.6 Hz, 1H), 7.38 (s, 1H), 7.43(s, 1H), 7.48 (t, J=7.8 Hz, 1H), 7.57 (s, 1H), 7.65-7.67 (m, 1H), 8.35(d, J=5.4 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 446 (M+1)⁺

Compound 4482-[6-Methoxy-4-(5,6,6′-trimethyl-[2,2′]bipyridin-3-yloxy)-quinolin-7-yloxymethyl]-propane-1,3-diol

6-Methoxy-4-(5,6,6′-trimethyl-[2,2′]bipyridin-3-yloxy)-quinolin-7-ol(compound 443) (75 mg) was dissolved in tetrahydrofuran (2 ml) toprepare a solution. Triphenylphosphine (102 mg),(2,2-dimethyl-[1,3]dioxan-5-yl)-methanol (34 mg), anddiethylazodicarboxylate (0.07 ml) were added to the solution, and themixture was stirred at room temperature for 7 hr. Further, 1N-sulfuricacid (4 ml) was added to the reaction solution, and the mixture wasstirred at room temperature overnight. The reaction solution was broughtto 0° C., was stirred, and was made alkaline by the addition of a 10%aqueous sodium hydroxide solution. Water was added thereto, and themixture was extracted with ethyl acetate. The ethyl acetate layer wasthen washed with saturated brine and was dried over anhydrous sodiumsulfate. The solvent was removed by distillation under the reducedpressure, and the residue was purified by thin layer chromatographyusing chloroform-methanol to give the title compound (56 mg, yield 62%).

¹H-NMR (CD₃OD, 400 MHz): δ 2.19 (s, 3H), 2.23-2.29 (m, 1H), 2.45 (s,3H), 2.63 (s, 3H), 3.80 (d, J=5.9 Hz, 4H), 4.00 (s, 3H), 4.24 (d, J=5.6Hz, 2H), 6.32 (d, J=5.4 Hz, 1H), 7.04-7.06 (m, 1H), 7.30 (s, 1H),7.57-7.65 (m, 4H), 8.24 (d, J=5.4 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 476 (M+1)⁺

Compound 4493-[6-Methoxy-4-(5,6,6′-trimethyl-[2,2′]bipyridin-3-yloxy)-quinolin-7-yloxy]-propane-1,2-diol

3-(6-Methoxy-7-oxiranylmethoxy-quinolin-4-yloxy)-5,6,6′-trimethyl-[2,2′]bipyridine(compound 446) (75 mg) was dissolved in methylene chloride (2 ml) toprepare a solution. The solution was brought to 0° C., trifluoroaceticacid (1 ml) was added thereto, and the mixture was stirred at 0° C. for30 min and then at room temperature for 4 hr. The reaction solution wasbrought to 0° C., was stirred and was made alkaline by the addition of a10% aqueous sodium hydroxide solution. Water was added thereto, and themixture was extracted with chloroform. The chloroform layer was thenwashed with saturated brine and was dried over anhydrous sodium sulfate.The solvent was removed by distillation under the reduced pressure, andthe residue was purified by thin layer chromatography usingchloroform-methanol to give the title compound (48 mg, yield 61%).

¹H-NMR (CD₃OD, 400 MHz): δ 2.18 (s, 3H), 2.45 (s, 3H), 2.63 (s, 3H),3.69-3.78 (m, 2H), 4.01 (s, 3H), 4.07-4.15 (m, 2H), 4.21-4.24 (m, 1H),6.33 (d, J=5.4 Hz, 1H), 7.03-7.06 (m, 1H), 7.29 (s, 1H), 7.58-7.65 (m,4H), 8.25 (d, J=5.6 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 462 (M+1)⁺

Compound 4502-[6-Methoxy-4-(5,6,6′-trimethyl-[2,2′]bipyridin-3-yloxy)-quinolin-7-yloxy]-ethanol

6-Methoxy-4-(5,6,6′-trimethyl-[2,2′]bipyridin-3-yloxy)-quinolin-7-ol(compound 443) (50 mg) was dissolved in N,N-dimethylformamide (2 ml) toprepare a solution. Potassium carbonate (54 mg) and 2-bromoethanol (0.03ml) were added to the solution, and the mixture was stirred at 70° C.overnight. The solvent was removed by distillation under the reducedpressure, water was then added to the residue, and the mixture wasextracted with chloroform. The chloroform layer was washed withsaturated brine and was dried over anhydrous sodium sulfate. The solventwas removed by distillation under the reduced pressure, and the residuewas purified by thin layer chromatography using chloroform-acetone togive the title compound (29 mg, yield 51%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.17 (s, 3H), 2.39 (s, 3H), 2.64 (s, 3H),4.01 (s, 3H), 4.09 (t, J=4.1 Hz, 2H), 4.29 (t, J=4.9 Hz, 2H), 6.33 (d,J=5.4 Hz, 1H), 6.93 (d, J=8.1 Hz, 1H), 7.39 (s, 1H), 7.43 (s, 1H),7.46-7.50 (m, 1H), 7.58 (s, 1H), 7.65-7.67 (m, 1H), 8.35 (d, J=5.4 Hz,1H)

Mass spectrometric value (ESI−MS, m/z): 432 (M+1)⁺

Compound 4511-{2-[6-Methoxy-4-(2-methyl-[1,8]naphthyridin-3-yloxy)-quinolin-7-yloxy]-ethyl}-piperidine4-ol

3-[7-(2-Chloro-ethoxy)-6-methoxy-quinolin-4-yloxy]-2-methyl-[1,8]naphthyridine(compound 398) (32 mg) was suspended in N,N-dimethylformamide (2 ml).Potassium carbonate (34 mg) and 4-hydroxypiperidine (25 mg) were addedto the suspension, and the mixture was stirred at 80° C. overnight. Thesolvent was removed by distillation under the reduced pressure, waterwas then added to the residue, and the mixture was extracted withchloroform. The chloroform layer was washed with saturated brine and wasdried over anhydrous sodium sulfate. The solvent was removed bydistillation under the reduced pressure, and the residue was purified bythin layer chromatography using chloroform-methanol to give the titlecompound (22 mg, yield 60%).

¹H-NMR (CDCl₃, 400 MHz): δ 1.25-2.48 (m, 8H), 2.77 (s, 3H), 3.03 (s,2H), 3.80 (s, 1H), 4.02 (s, 3H), 4.40 (s, 2H), 6.44 (d, J=5.1 Hz, 1H),7.47-7.51 (m, 2H), 7.53 (s, 1H), 7.77 (s, 1H), 8.11 (dd, J=2.0 Hz, 8.3Hz, 1H), 8.54 (d, J=5.1 Hz, 1H), 9.11 (dd, J=2.0 Hz, 4.4 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 461 (M+1)⁺

Compound 4523-(7-Benzyloxy-6-methoxy-quinolin-4-yloxy)-5,6,5′-trimethyl-[2,2′]bipyridine

5,6,5′-Trimethyl-[2,2′]bipyridin-3-ol (300 mg),7-benzyloxy-4-chloro-6-methoxyquinoline (1.26 g),4-dimethylaminopyridine (513 mg), and cesium carbonate (1.37 g) weresuspended in dimethyl sulfoxide (6 ml), and the suspension was stirredat 130° C. overnight. The reaction solution was cooled to roomtemperature, water was then added to the reaction solution, and themixture was extracted with chloroform. The chloroform layer was thenwashed with saturated brine and was dried over anhydrous sodium sulfate.The solvent was removed by distillation under the reduced pressure, andthe residue was purified by column chromatography usingchloroform-methanol to give the title compound (504 mg, yield 75%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.24 (s, 3H), 2.37 (s, 3H), 2.65 (s, 3H),4.04 (s, 3H), 5.32 (s, 2H), 6.35 (d, J=5.4 Hz, 1H), 7.31-7.53 (m, 8H),7.58 (s, 1H), 7.72 (d, J=7.8 Hz, 1H), 8.33 (s, 1H), 8.35 (d, J=5.4 Hz,1H)

Mass spectrometric value (ESI−MS, m/z): 478 (M+1)⁺

Compound 4536-Methoxy-4-(5,6,5′-trimethyl-[2,2′]bipyridin-3-yloxy)-quinolin-7-ol

3-(7-Benzyloxy-6-methoxy-quinolin-4-yloxy)-5,6,5′-trimethyl-[2,2′]bipyridine(compound 452) (500 mg) was dissolved in trifluoroacetic acid (5 ml) toprepare a solution. Methanesulfonic acid (0.5 ml) was added to thesolution, and the mixture was stirred at 70° C. for 1.5 hr. The reactionsolution was cooled to room temperature, and the solvent was removed bydistillation under the reduced pressure. An aqueous sodiumhydrogencarbonate solution was then added to the residue, and themixture was extracted with chloroform. The chloroform layer was washedwith saturated brine and was dried over anhydrous sodium sulfate. Thesolvent was removed by distillation under the reduced pressure, and theresidue was purified by thin layer chromatography usingchloroform-methanol to give the title compound (358 mg, yield 88%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.24 (s, 3H), 2.37 (s, 3H), 2.65 (s, 3H),4.06 (s, 3H), 6.33 (d, J=5.4 Hz, 1H), 7.34 (s, 1H), 7.38-7.41 (m, 1H),7.55 (s, 1H), 7.59 (s, 1H), 7.70-7.72 (m, 1H), 8.33 (s, 1H), 8.39 (d,J=5.4 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 388 (M+1)⁺

Compound 4547-Benzyloxy-4-[2-(4,5-dimethyl-thiazol-2-yl)-5,6-dimethyl-pyridin-3-yloxy]-6-methoxy-quinoline

2-(4,5-Dimethyl-thiazol-2-yl)-5,6-dimethyl-pyridin-3-ol (200 mg),7-benzyloxy-4-chloro-6-methoxyquinoline (768 mg),4-dimethylaminopyridine (313 mg), and cesium carbonate (313 mg) weresuspended in dimethyl sulfoxide (4 ml), and the mixture was stirred at130° C. for 9 hr. The reaction solution was cooled to room temperature,water was then added to the reaction solution, and the mixture wasextracted with chloroform. The chloroform layer was washed withsaturated brine and was dried over anhydrous sodium sulfate. The solventwas removed by distillation under the reduced pressure, and the residuewas purified by column chromatography using chloroform-methanol to givethe title compound (94 mg, yield 22%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.10 (s, 3H), 2.27 (d, J=0.7 Hz, 3H), 2.35(s, 3H), 2.63 (s, 3H), 4.07 (s, 3H), 5.35 (s, 2H), 6.32 (d, J=5.4 Hz,1H), 7.32-7.35 (m, 2H), 7.39-7.42 (m, 2H), 7.53-7.55 (m, 3H), 7.72 (s,1H), 8.39 (d, J=5.4 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 498 (M+1)⁺

Compound 4554-[2-(4,5-Dimethyl-thiazol-2-yl)-5,6-dimethyl-pyridin-3-yloxy]-6-methoxy-quinolin-7-ol

7-Benzyloxy-4-[2-(4,5-dimethyl-thiazol-2-yl)-5,6-dimethyl-pyridin-3-yloxy]-6-methoxy-quinoline(compound 454) (254 mg) was dissolved in trifluoroacetic acid (3 ml) toprepare a solution. Methanesulfonic acid (0.3 ml) was added to thesolution, and the mixture was stirred at 70° C. for one hr. The reactionsolution was cooled to room temperature, and the solvent was removed bydistillation under the reduced pressure. An aqueous sodiumhydrogencarbonate solution was then added to the residue, and themixture was extracted with chloroform. The chloroform layer was washedwith saturated brine and was dried over anhydrous sodium sulfate. Thesolvent was removed by distillation under the reduced pressure, and theresidue was purified by thin layer chromatography usingchloroform-methanol to give the title compound (189 mg, yield 91%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.10 (s, 3H), 2.27 (s, 3H), 2.36 (s, 3H),2.63 (s, 3H), 4.10 (s, 3H), 6.31 (d, J=5.4 Hz, 1H), 7.33 (s, 1H), 7.61(s, 1H), 7.73 (s, 1H), 8.42 (d, J=5.4 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 408 (M+1)⁺

Compound 4561-{3-[7-(3-Hydroxy-propoxy)-6-methoxy-quinolin-4-yloxy]-quinolin-2-yl}-ethanone

1-[3-(7-Hydroxy-6-methoxy-quinolin-4-yloxy)-quinolin-2-yl]-ethanone(compound 390) (50 mg) was dissolved in N,N-dimethylformamide (2 ml) toprepare a solution. Potassium carbonate (58 mg) and 3-bromo-1-propanol(0.03 ml) were added to the solution, and the mixture was stirred atroom temperature overnight. The solvent was removed by distillationunder the reduced pressure, water was then added to the residue, and themixture was extracted with chloroform. The chloroform layer was washedwith saturated brine and was dried over anhydrous sodium sulfate. Thesolvent was removed by distillation under the reduced pressure, and theresidue was purified by thin layer chromatography usingchloroform-acetone to give the title compound (44 mg, yield 74%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.18-2.23 (m, 2H), 2.77 (s, 3H), 3.94 (t,J=5.4 Hz, 2H), 4.04 (s, 3H), 4.41 (t, J=5.8 Hz, 2H), 6.37 (d, J=5.4 Hz,1H), 7.52 (s, 1H), 7.63 (s, 1H), 7.68-7.72 (m, 1H), 7.79-7.84 (m, 2H),7.98 (s, 1H), 8.24 (d, J=8.5 Hz, 1H), 8.47 (d, J=5.4 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 419 (M+1)⁺

Compound 4573-(6-Methoxy-7-oxiranylmethoxy-quinolin-4-yloxy)-5,6,5′-trimethyl-[2,2′]bipyridine

6-Methoxy-4-(5,6,5′-trimethyl-[2,2′]bipyridin-3-yloxy)-quinolin-7-ol(compound 453) (50 mg) was suspended in N,N-dimethylformamide (2 ml).Potassium carbonate (54 mg) and epibromohydrin (0.03 ml) were added tothe suspension, and the mixture was stirred at room temperatureovernight. The solvent was removed by distillation under the reducedpressure, water was then added to the residue, and the mixture wasextracted with chloroform. The chloroform layer was washed withsaturated brine and was dried over anhydrous sodium sulfate. The solventwas removed by distillation under the reduced pressure, and the residuewas purified by thin layer chromatography using chloroform-methanol togive the title compound (58 mg, yield 100%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.24 (s, 3H), 2.38 (s, 3H), 2.65 (s, 3H),2.84-2.85 (m, 1H), 2.95-2.98 (m, 1H), 3.48-3.52 (m, 1H), 4.03 (s, 3H),4.14-4.19 (m, 1H), 4.45 (dd, J=3.2 Hz, 11.5 Hz, 1H), 6.36 (d, J=5.4 Hz,1H), 7.35 (s, 1H), 7.38-7.40 (m, 1H), 7.45 (s, 1H), 7.58 (s, 1H), 7.73(d, J=8.1 Hz, 1H), 8.30 (s, 1H), 8.37 (d, J=5.4 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 444 (M+1)⁺

Compound 4584-[2-(4,5-Dimethyl-thiazol-2-yl)-5,6-dimethyl-pyridin-3-yloxy]-6-methoxy-7-oxiranylmethoxy-quinoline

4-[2-(4,5-Dimethyl-thiazol-2-yl)-5,6-dimethyl-pyridin-3-yloxy]-6-methoxy-quinolin-7-ol(compound 455) (41 mg) was suspended in N,N-dimethylformamide (2 ml).Potassium carbonate (42 mg) and epibromohydrin (0.03 ml) were added tothe suspension, and the mixture was stirred at room temperatureovernight. The solvent was removed by distillation under the reducedpressure, water was then added to the residue, and the mixture wasextracted with chloroform. The chloroform layer was washed withsaturated brine and was dried over anhydrous sodium sulfate. The solventwas removed by distillation under the reduced pressure, and the residuewas purified by thin layer chromatography using chloroform-methanol togive the title compound (44 mg, yield 94%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.08 (s, 3H), 2.27 (s, 3H), 2.36 (s, 3H),2.64 (s, 3H), 2.85-2.87 (m, 1H), 2.97-2.99 (m, 1H), 3.51-3.55 (m, 1H),4.06 (s, 3H), 4.17-4.22 (m, 1H), 4.48 (dd, J=3.2 Hz, 11.2 Hz, 1H), 6.33(d, J=5.4 Hz, 1H), 7.34 (s, 1H), 7.50 (s, 1H), 7.72 (s, 1H), 8.40 (d,J=5.4 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 486 (M+Na)⁺

Compound 4592-[6-Methoxy-4-(5,6,5′-trimethyl-[2,2′]bipyridin-3-yloxy)-quinolin-7-yloxy]-ethanol

6-Methoxy-4-(5,6,5′-trimethyl-[2,2′]bipyridin-3-yloxy)-quinolin-7-ol(compound 453) (50 mg) was suspended in N,N-dimethylformamide (2 ml).Potassium carbonate (54 mg) and 2-bromoethanol (0.03 ml) were added tothe suspension, and the mixture was stirred at 70° C. overnight. Thesolvent was removed by distillation under the reduced pressure, waterwas then added to the residue, and the mixture was extracted withchloroform. The chloroform layer was washed with saturated brine and wasdried over anhydrous sodium sulfate. The solvent was removed bydistillation under the reduced pressure, and the residue was purified bythin layer chromatography using chloroform-acetone to give the titlecompound (34 mg, yield 61%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.24 (s, 3H), 2.38 (s, 3H), 2.65 (s, 3H),4.02 (s, 3H), 4.09-4.10 (m, 2H), 4.30 (t, J=4.6 Hz, 2H), 6.36 (d, J=5.4Hz, 1H), 7.35 (s, 1H), 7.37-7.40 (m, 1H), 7.44 (s, 1H), 7.58 (s, 1H),7.72 (d, J=8.1 Hz, 1H), 8.32 (s, 1H), 8.38 (d, J=5.1 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 432 (M+1)⁺

Compound 4603-[6-Methoxy-4-(5,6,5′-trimethyl-[2,2′]bipyridin-3-yloxy)-quinolin-7-yloxy]-propan-1-ol

6-Methoxy-4-(5,6,5′-trimethyl-[2,2′]bipyridin-3-yloxy)-quinolin-7-ol(compound 453) (50 mg) was suspended in N,N-dimethylformamide (2 ml).Potassium carbonate (54 mg) and 3-bromo-1-propanol (0.03 ml) were addedto the suspension, and the mixture was stirred at room temperatureovernight. The solvent was removed by distillation under the reducedpressure, water was then added to the residue, and the mixture wasextracted with chloroform. The chloroform layer was washed withsaturated brine and was dried over anhydrous sodium sulfate. The solventwas removed by distillation under the reduced pressure, and the residuewas purified by thin layer chromatography using chloroform-acetone togive the title compound (26 mg, yield 46%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.16-2.22 (m, 2H), 2.24 (s, 3H), 2.38 (s,3H), 2.65 (s, 3H), 3.93 (s, 2H), 4.01 (s, 3H), 4.38 (t, J=5.9 Hz, 2H),6.36 (d, J=5.4 Hz, 1H), 7.35 (s, 1H), 7.38-7.44 (m, 2H), 7.56 (s, 1H),7.72 (d, J=8.1 Hz, 1H), 8.32 (s, 1H), 8.37 (d, J=5.4 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 446 (M+1)⁺

Compound 4612-{4-[2-(4,5-Dimethyl-thiazol-2-yl)-5,6-dimethyl-pyridin-3-yloxy]-6-methoxy-quinolin-7-yloxy}-ethanol

4-[2-(4,5-Dimethyl-thiazol-2-yl)-5,6-dimethyl-pyridin-3-yloxy]-6-methoxy-quinolin-7-ol(compound 455) (41 mg) was suspended in N,N-dimethylformamide (2 ml).Potassium carbonate (42 mg) and 2-bromoethanol (0.02 ml) were added tothe suspension, and the mixture was stirred at 70° C. overnight. Thesolvent was removed by distillation under the reduced pressure, waterwas then added to the residue, and the mixture was extracted withchloroform. The chloroform layer was washed with saturated brine and wasdried over anhydrous sodium sulfate. The solvent was removed bydistillation under the reduced pressure, and the residue was purified bythin layer chromatography using chloroform-acetone to give the titlecompound (47 mg, yield 100%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.08 (s, 3H), 2.27 (s, 3H), 2.36 (s, 3H),2.64 (s, 3H), 4.05 (s, 3H), 4.11 (t, J=4.4 Hz, 2H), 4.33 (t, J=4.4 Hz,2H), 6.34 (d, J=5.4 Hz, 1H), 7.34 (s, 1H), 7.52 (s, 1H), 7.72 (s, 1H),8.41 (d, J=5.4 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 452 (M+1)⁺

Compound 4623-{4-[2-(4,5-Dimethyl-thiazol-2-yl)-5,6-dimethyl-pyridin-3-yloxy]-6-methoxy-quinolin-7-yloxy}-propan-1-ol

4-[2-(4,5-Dimethyl-thiazol-2-yl)-5,6-dimethyl-pyridin-3-yloxy]-6-methoxy-quinolin-7-ol(compound 455) (41 mg) was suspended in N,N-dimethylformamide (2 ml).Potassium carbonate (42 mg) and 3-bromo-1-propanol (0.03 ml) were addedto the suspension, and the mixture was stirred at room temperatureovernight. The solvent was removed by distillation under the reducedpressure, water was then added to the residue, and the mixture wasextracted with chloroform. The chloroform layer was washed withsaturated brine and was dried over anhydrous sodium sulfate. The solventwas removed by distillation under the reduced pressure, and the residuewas purified by thin layer chromatography using chloroform-acetone togive the title compound (32 mg, yield 68%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.09 (s, 3H), 2.18-2.24 (m, 2H), 2.27 (s,3H), 2.36 (s, 3H), 2.64 (s, 3H), 3.94-3.95 (m, 2H), 4.04 (s, 3H), 4.41(t, J=5.9 Hz, 2H), 6.34 (d, J=5.4 Hz, 1H), 7.34 (s, 1H), 7.51 (s, 1H),7.70 (s, 1H), 8.40 (d, J=5.4 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 466 (M+1)⁺

Compound 4633-[6-Methoxy-4-(5,6,5′-trimethyl-[2,2′]bipyridin-3-yloxy)-quinolin-7-yloxy]-propane-1,2-diol

3-(6-Methoxy-7-oxiranylmethoxy-quinolin-4-yloxy)-5,6,5′-trimethyl-[2,2′]bipyridine(compound 457) (54 mg) was dissolved in methylene chloride (2 ml) toprepare a solution which was then brought to 0° C. Trifluoroacetic acid(1 ml) was added thereto, and the mixture was stirred at 0° C. for 30min and then at room temperature for 5 hr. The reaction solution wasbrought to 0° C., was stirred and was made alkaline by the addition of a10% aqueous sodium hydroxide solution. Water was added to the reactionsolution, the mixture was extracted with chloroform, and the chloroformlayer was then washed with saturated brine and was dried over anhydroussodium sulfate. The solvent was removed by distillation under thereduced pressure, and the residue was purified by thin layerchromatography using chloroform-methanol to give the title compound (35mg, yield 63%).

¹H-NMR (CD₃OD, 400 MHz): δ 2.24 (s, 3H), 2.44 (s, 3H), 2.62 (s, 3H),3.69-3.78 (m, 2H), 4.02 (s, 3H), 4.06-4.15 (m, 2H), 4.21-4.24 (m, 1H),6.34 (d, J=5.4 Hz, 1H), 7.29 (s, 1H), 7.56-7.58 (m, 1H), 7.61 (s, 1H),7.66 (s, 1H), 7.69-7.71 (m, 1H), 8.24 (s, 1H), 8.27 (d, J=5.4 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 484 (M+Na)⁺

Compound 4643-{4-[2-(4,5-Dimethyl-thiazol-2-yl)-5,6-dimethyl-pyridin-3-yloxy]-6-methoxy-quinolin-7-yloxy}-propane-1,2-diol

4-[2-(4,5-Dimethyl-thiazol-2-yl)-5,6-dimethyl-pyridin-3-yloxy]-6-methoxy-7-oxiranylmethoxy-quinoline(compound 458) (40 mg) was dissolved in methylene chloride (2 ml) toprepare a solution which was then brought to 0° C. Trifluoroacetic acid(0.4 ml) was added thereto, the mixture was stirred at 0° C. for 30 min,and the mixture was then stirred at room temperature for 5 hr. Thereaction solution was brought to 0° C., was stirred, and was madealkaline by the addition of a 10% aqueous sodium hydroxide solution.Water was added to the reaction solution, the mixture was extracted withchloroform, and the chloroform layer was then washed with saturatedbrine and was dried over anhydrous sodium sulfate. The solvent wasremoved by distillation under the reduced pressure, and the residue waspurified by thin layer chromatography using chloroform-methanol to givethe title compound (41 mg, yield 100%).

¹H-NMR (CD₃OD, 400 MHz): δ 1.98 (s, 3H), 2.27 (s, 3H), 2.40 (s, 3H),2.60 (s, 3H), 3.71-3.80 (m, 2H), 4.04 (s, 3H), 4.10-4.19 (m, 2H),4.25-4.28 (m, 1H), 6.34 (d, J=5.4 Hz, 1H), 7.37 (s, 1H), 7.56 (s, 1H),7.81 (s, 1H), 8.31 (d, J=5.4 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 504 (M+Na)

Compound 4653-[7-(2-Chloro-ethoxy)-6-methoxy-quinolin-4-yloxy]-5,6,6′-trimethyl-[2,2′]bipyridine

6-Methoxy-4-(5,6,6′-trimethyl-[2,2′]bipyridin-3-yloxy)-quinolin-7-ol(compound 443) (30 mg) was dissolved in N,N-dimethylformamide (2 ml) toprepare a solution. Potassium carbonate (107 mg) and1-bromo-2-chloroethane (0.03 ml) were added to the solution, and themixture was stirred at room temperature overnight. The solvent wasremoved by distillation under the reduced pressure, water was then addedto the residue, and the mixture was extracted with chloroform. Thechloroform layer was washed with saturated brine and was dried overanhydrous sodium sulfate. The solvent was removed by distillation underthe reduced pressure, and the residue was purified by thin layerchromatography using chloroform-methanol to give the title compound (37mg, yield 100%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.14 (s, 3H), 2.39 (s, 3H), 2.65 (s, 3H),3.96 (t, J=6.1 Hz, 2H), 4.03 (s, 3H), 4.45 (t, J=5.9 Hz, 2H), 6.35 (d,J=5.4 Hz, 1H), 6.93 (d, J=7.3 Hz, 1H), 7.39 (s, 1H), 7.46-7.52 (m, 2H),7.60 (s, 1H), 7.68 (d, J=7.8 Hz, 1H), 8.35 (d, J=5.6 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 472 (M+Na)⁺

Compound 4663-[7-(2-Chloro-ethoxy)-6-methoxy-quinolin-4-yloxy]-5,6,5′-trimethyl-[2,2′]bipyridine

6-Methoxy-4-(5,6,5′-trimethyl-[2,2′]bipyridin-3-yloxy)-quinolin-7-ol(compound 453) (30 mg) was suspended in N,N-dimethylformamide (2 ml).Potassium carbonate (107 mg) and 1-bromo-2-chloroethane (0.03 ml) wereadded to the suspension, and the mixture was stirred at room temperatureovernight. The solvent was removed by distillation under the reducedpressure, water was then added to the residue, and the mixture wasextracted with chloroform. The chloroform layer was washed withsaturated brine and was dried over anhydrous sodium sulfate. The solventwas removed by distillation under the reduced pressure, and the residuewas purified by thin layer chromatography using chloroform-methanol togive the title compound (36 mg, yield 100%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.24 (s, 3H), 2.38 (s, 3H), 2.65 (s, 3H),3.96 (t, J=6.1 Hz, 2H), 4.03 (s, 3H), 4.45 (t, J=6.1 Hz, 2H), 6.37 (d,J=5.4 Hz, 1H), 7.35 (s, 1H), 7.38-7.40 (m, 1H), 7.44 (s, 1H), 7.59 (s,1H), 7.73 (d, J=7.8 Hz, 1H), 8.30 (s, 1H), 8.38 (d, J=5.6 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 472 (M+Na)⁺

Compound 4671-{3-[6-Methoxy-7-(2-piperidin-1-yl-ethoxy)-quinolin-4-yloxy]-quinolin-2-yl}-ethanone

1-{3-[7-(2-Chloro-ethoxy)-6-methoxy-quinolin-4-yloxy]-quinolin-2-yl}-ethanone(41 mg) was dissolved in N,N-dimethylformamide (2 ml) to prepare asolution. Potassium carbonate (268 mg) and piperidine (0.1 ml) wereadded to the solution, and the mixture was stirred at 80° C. for 2 days.The solvent was removed by distillation under the reduced pressure,water was then added to the residue, and the mixture was extracted withchloroform. The chloroform layer was washed with saturated brine and wasdried over anhydrous sodium sulfate. The solvent was removed bydistillation under the reduced pressure, and the residue was purified bythin layer chromatography using chloroform-methanol to give the titlecompound (24 mg, yield 53%).

¹H-NMR (CDCl₃, 400 MHz): δ 1.23-2.64 (m, 10H), 2.77 (s, 3H), 3.01 (s,2H), 4.03 (s, 3H), 4.39 (s, 2H), 6.36 (d, J=5.1 Hz, 1H), 7.45 (s, 1H),7.62 (s, 1H), 7.66-7.70 (m, 1H), 7.78-7.82 (m, 2H), 7.95 (s, 1H), 8.24(d, J=8.5 Hz, 1H), 8.48 (d, J=5.1 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 472 (M+1)⁺

Compound 4682-{2-[6-Methoxy-4-(5,6,6′-trimethyl-[2,2′]bipyridin-3-yloxy)-quinolin-7-yloxy]-ethylamino}-ethanol

3-[7-(2-Chloro-ethoxy)-6-methoxy-quinolin-4-yloxy]-5,6,6′-trimethyl-[2,2′]bipyridine(compound 465) (35 mg) was dissolved in N,N-dimethylformamide (2 ml) toprepare a solution. Potassium carbonate (108 mg) and 2-aminoethanol(0.14 ml) were added to the solution, and the mixture was stirred at 70°C. overnight. The solvent was removed by distillation under the reducedpressure, water was then added to the residue, and the mixture wasextracted with chloroform. The chloroform layer was washed withsaturated brine and was dried over anhydrous sodium sulfate. The solventwas removed by distillation under the reduced pressure, and the residuewas purified by thin layer chromatography using chloroform-methanol togive the title compound (24 mg, yield 64%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.20 (s, 3H), 2.39 (s, 3H), 2.64 (s, 3H),2.95 (t, J=5.9 Hz, 2H), 3.22 (t, J=5.1 Hz, 2H), 3.73 (t, J=5.6 Hz, 2H),4.00 (s, 3H), 4.31 (t, J=5.1 Hz, 2H), 6.31 (d, J=5.1 Hz, 1H), 6.93 (d,J=7.6 Hz, 1H), 7.38 (d, J=4.6 Hz, 2H), 7.48 (t, J=7.6 Hz, 1H), 7.57 (s,1H), 7.64 (d, J=7.8 Hz, 1H), 8.35 (d, J=5.1 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 475 (M+1)⁺

Compound 4692-{2-[6-Methoxy-4-(5,6,5′-trimethyl-[2,2′]bipyridin-3-yloxy)-quinolin-7-yloxy]-ethylamino}-ethanol

3-[7-(2-Chloro-ethoxy)-6-methoxy-quinolin-4-yloxy]-5,6,5′-trimethyl-[2,2′]bipyridine(compound 466) (33 mg) was dissolved in N,N-dimethylformamide (2 ml) toprepare a solution. Potassium carbonate (101 mg) and 2-aminoethanol(0.13 ml) were added to the solution, and the mixture was stirred at 70°C. overnight. The solvent was removed by distillation under the reducedpressure, water was then added to the residue, and the mixture wasextracted with chloroform. The chloroform layer was washed withsaturated brine and was dried over anhydrous sodium sulfate. The solventwas removed by distillation under the reduced pressure, and the residuewas purified by thin layer chromatography using chloroform-methanol togive the title compound (25 mg, yield 71%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.24 (s, 3H), 2.37 (s, 3H), 2.65 (s, 3H),2.95 (t, J=5.1 Hz, 2H), 3.22 (t, J=5.1 Hz, 2H), 3.73 (t, J=5.1 Hz, 2H),4.01 (s, 3H), 4.32 (t, J=5.4 Hz, 2H), 6.34 (d, J=5.1 Hz, 1H), 7.34 (s,1H), 7.37-7.40 (m, 2H), 7.56 (s, 1H), 7.70 (d, J=8.1 Hz, 1H), 8.35-8.36(m, 1H), 8.38 (d, J=5.4 Hz, 1H)

Mass spectrometric value (ESI−MS, m/z): 475 (M+1)⁺

Evaluation Tests Test Example 1 TGFβ Signal Inhibitory Activity (InVitro Test)

The TGFβ signal inhibitory activity of compounds according to thepresent invention was evaluated according to the method described in J.Biol. Chem., 273, 21145-21152 (1998).

Specifically, a luciferase gene driving by four tandem binding sequencesof Smad2/3, which are TGFβ signal transfer factors was used as areporter gene ((SBE)4-Luc). This reporter gene was introduced into humanlung cancer epithelial cells (A549) (available from ATCC) to establish astable cell line expressing its gene.

A test compound and TGFβ-1 (2 ng/ml) were added to the cells, and themixture was cultured for 4 hr. Compounds according to the presentinvention synthesized in the above working examples were used as thetest compound. After the culture, the luciferase activity of cells wasmeasured by a chemiluminescence method (Steady Glo (trademark)luciferase assay system available from Promega).

Likewise, the luciferase activity was measured for control cells, thatis, cells which had been cultured with the addition of TGFβ only, andcells which had been cultured without the addition of TGFβ and the testcompound.

The TGFβ inhibition rate (%) was calculated based on the results ofmeasurement according to the following equation:

TGFβ inhibition rate(%)=(A−B)/(A−C)×100

wherein A, B and C have the following respective meanings:

A: luciferase activity in the case where TGFβ1 was added and the testcompound was not added (relative luciferase unit);

B: luciferase activity in the case where both TGFβ1 and the testcompound were added (relative luciferase unit); and

C: luciferase activity in the case where neither TGFβ1 nor the testcompound was added (relative luciferase unit).

The test was carried out for each of a test compound concentration of 3μM and a test compound concentration of 10 μM. For given test compounds,the test was further carried out for a test compound concentration of 1μM.

The results were as shown in Table 1.

The results show that the compounds according to the present inventionhave activity which counteracts the action of TGFβ.

TABLE 1 TGFβ inhibition, % Compound Molecular structure 10 μM 3 μM 1

53 5 2

88 13 3

75 0 4

78 20 5

56 13 6

72 30 7

54 13 8

59 10 9

77 29 10

87 38 11

66 28 12

89 21 13

78 28 14

64 15 15

84 41 16

62 0 17

80 15 18

69 15 19

95 73 20

69 19 21

71 16 22

81 11 23

91 56 24

91 66 25 26

73 20 27

93 0 28

53 0 29

67 0 30

61 0 31

98 49 32

98 81 33

94 27 34

78 0 35

89 49 36

100 95 37

100 94 38

100 98 39

91 0 40

83 12 41

97 57 42

93 90 43

66 0 44

100 97 45

67 0 46

100 70 47

98 45 48

100 98 49

62 0 50

100 100 51

99 71 52

100 97 53

100 97 54

73 13 55

98 53 56

84 0 57

55 10 58

100 90 59

99 65 60

98 63 61

98 61 62

85 43 63

91 57 64

98 67 65

100 58 66

86 22 67

93 4 68

100 89 69

100 100 70

100 73 71

100 79 72

100 98 73

81 24 74

84 27 75

100 97 76

100 95 77

46 0 78

57 0 79

100 97 80

95 62 81

100 91 82

99 90 83

81 41 84

100 84 85

100 87 86

99 68 87

99 84 88

94 70 89

63 20 90

95 54 91

100 96 92

82 25 93

88 44 94

97 39 95

96 67 96

65 19 97

92 14 98

93 4 99

92 7 100

82 0 101

64 0 102

95 33 103

84 20 104

58 0 105

88 17 106

80 9 107

82 0 108

73 0 109

66 5 110

93 55 111

92 29 112

91 44 113

96 0 114

96 0 115

97 74 116

100 99 117

98 84 118

100 97 119

97 96 120

100 94 121

100 100 122

100 100 123

100 98 124

100 99 125

100 98 126

100 100 127

100 99 128

100 100 129

100 100 130

100 90 131

100 96 132

99 72 133

100 100 134

100 100 135

100 100 136

100 90 137

100 100 138

100 96 139

100 99 140

100 85 141

89 55 142

100 100 143

100 97 144

100 99 145

100 87 146

100 64 147

100 98 148

100 99 149

100 96 150

100 97 151

100 95 152

100 99 153

100 100 154

100 99 155

100 100 156

100 99 157

100 100 158

100 100 159

100 98 160

100 98 161

83 25 162

54 5 163

67 3 TGFβ inhibition, % Compound Molecular structure 10 μM 3 μM 1 μM 164

98 54 165

89 38 166

67 24 167

100 98 168

74 22 169

100 99 170

100 76 171

76 11 172

99 82 173

100 83 174

96 57 175

60 13 176

67 32 177

100 94 178

97 66 179

68 18 180

55 −2 181

82 42 182

96 57 183

100 82 184

100 100 185

59 11 186

100 76 187

91 35 188

100 80 189

100 86 190

86 30 191

93 39 192

99 79 193

99 74 194

94 47 195

100 99 196

83 41 197

88 40 198

80 32 199

59 14 200

100 94 201

100 79 202

54 20 203

52 19 204

77 14 205

57 26 206

94 69 207

99 77 208

73 18 209

100 99 210

80 45 211

100 87 212

100 94 213

65 28 214

100 99 215

99 72 216

73 22 217

100 91 218

56 21 219

67 20 220

100 99 221

98 71 222

100 44 223

100 99 224

96 69 225

78 39 226

96 60 227

87 50 228

100 88 229

100 99 230

97 60 231

100 100 232

79 66 233

100 98 234

100 87 235

100 100 236

100 90 237

100 100 238

100 92 239

100 83 240

100 100 241

100 96 242

99 68 243

62 −7 244

63 −3 245

99 80 246

93 64 247

100 93 248

100 99 249

98 52 250

81 34 251

100 84 252

78 16 253

97 68 254

100 100 255

100 93 256

100 98 257

62 15 258

100 99 259

100 260

100 96 261

100 100 262

100 91 263

99 82 264

100 88 265

85 45 266

100 92 267

83 34 268

100 100 269

97 270

100 271

100 94 272

100 98 273

100 99 274

97 275

90 45 276

100 89 277

89 32 278

99 90 279

100 98 280

88 45 281

100 88 282

100 96 283

100 99 284

100 96 285

100 65 286

100 93 287

100 100 288

100 94 289

99 80 290

57 18 291

78 14 292

100 86 293

95 65 294

77 53 295

96 47 296

100 86 297

94 61 298

75 30 299

100 99 300

63 9 301

75 20 302

90 30 303

96 304

64 26 305

64 28 306

53 20 307

69 26 308

56 21 309

79 41 310

97 72 311

90 53 312

76 50 313

94 56 314

89 50 315

100 98 316

100 99 317

100 100 318

100 82 319

100 100 320

100 100 321

100 100 322

88 50 323

100 89 324

100 86 325

60 19 326

100 83 327

100 89 328

100 100 329

100 100 330

100 100 331

90 73 332

100 97 333

100 334

99 335

100 336

100 337

98 338

100 92 339

100 340

99 341

99 342

89 343

93 344

92 345

93 61 346

99 347

100 348

76 349

96 350

96 351

90 42 352

68 14 353

86 54 354

100 100 355

100 100 356

54 −2 357

60 27 358

100 100 359

100 100 360

100 100 361

100 96 362

100 100 363

100 100 364

100 100 365

100 100 366

100 100 367

98 95 368

100 100 369

100 99 370

99 85 371

90 28 372

93 14 373

86 48 374

79 26 375

100 84 376

100 100 377

100 93 378

100 100 379

100 100 380

89 50 381

100 100 382

100 100 383

100 97 384

100 100 385

100 100 386

99 387

100 99 388

100 88 389

100 100 390

64 16 391

100 99 392

100 93 393

100 394

100 83 395

100 96 396

96 397

100 71 398

97 78 399

100 99 400

100 82 401

76 24 402

100 90 403

66 27 404

72 29 405

100 92 406

96 56 407

97 71 408

79 38 409

88 41 410

100 91 411

85 50 412

99 77 413

76 31 414

100 82 415

100 77 416

100 92 417

100 98 418

73 46 419

67 7 420

62 2 421

100 94 422

100 100 423

100 88 424

79 28 425

100 72 426

100 427

80 44 428

67 429

94 52 430

78 19 431

99 97 432

100 99 433

100 91 434

100 100 435

79 29 436

100 99 437

100 95 438

100 99 439

95 43 440

100 100 441

100 97 442

100 70 443

97 60 444

100 445

99 446

89 35 447

100 94 448

97 70 449

98 74 450

100 94 451

100 99 452

99 67 453

98 72 454

75 41 455

99 76 456

100 99 457

100 97 458

100 94 459

98 460

97 461

82 462

99 463

99 77 464

100 97 465

100 98 466

100 99 467

100 468

99 469

100

Test Example 2 Measurement of Fibrotic Inhibitory Activity Using MouseUnilateral Ureteral Obstruction (UUO) Model

The fibrotic inhibitory activity of a compound according to the presentinvention was evaluated using a mouse unilateral ureteral obstruction(UUO) model which is a renal fibrosis model. Compound 384 prepared inthe working example was used as the test compound.

Seven-week-old male BALB/c mice (available from Charles River Japan,Inc.) were purchased and were pre-raised before use in experiments.Regarding diets and drinking water, pellets CE-2 (available from CLEAJAPAN INC.) and sterile tap water were freely fed.

The mice underwent laparotomy under pentobarbital anesthesia, and theleft renal urinary duct was ligated. Thereafter, the mice underwentsuturing operation and were divided into a vehicle administration group(n=7) and a test compound administration group (n=7) using the weight asan index.

The test compound was weighed, and then one drop of 1 N HCl was added tothe test compound to prepare a solution. The solution was then suspendedin 0.5% carboxymethylcellulose (solvent). The suspension was forciblyorally administered twice a day with an oral sonde from the day ofurinary duct ligation (5, 15, or 50 mg/kg). The solvent was administeredto the vehicle administration group in the same manner as described justabove.

After administration for 4 days, the mouse left kidney was excised, andthe hydroxyproline content as an index of organ fibrosis was measured bythe following method.

Renal pieces were placed in 6 N HCl, were homogenized, and were thenheated on a heat block at 130° C. for 3 hr to hydrolyze protein.Thereafter, the suspension of renal pieces was neutralized by theaddition of an appropriate amount of 4 N NaOH. The neutralizedsuspension was centrifuged (1000 rpm, 5 min, room temperature) to obtainthe supernatant as a kidney extract. A chloramine T liquid, a perchloricacid solution (a solution prepared by adding distilled water to 31.5 mlof 60% perchloric acid to bring the total volume to 100 ml), and ap-dimethylaminobenzaldehyde solution (a solution prepared by addingmethylcellulose to 20 g of p-dimethylaminobenzaldehyde to bring thetotal volume to 100 ml) were added to the kidney extract, and a reactionwas allowed to proceed at 60° C. for 20 min. The absorbance at 557 nmwas then measured. The content of hydroxyproline was determined from themeasured data based on a calibration curve for hydroxyproline preparedusing control. Further, the content of hydroxyproline thus determinedwas corrected according to the weight of the homogenized kidney.

The results were as shown in Table 2. The values in the table areaverage of data on 7 mice for each group ±standard deviation.

As a result, it was found that, as compared with the kidney of normalmice, for the mouse kidney for which the left renal urinary duct hadbeen ligated, the content of hydroxyproline was increased andextracellular substrate accumulated within the kidney. As compared withthe solvent administration group, for the group to which the compoundaccording to the present invention had been administered, the content ofhydroxyproline was lowered, indicating that the compound according tothe present invention could suppress the accumulation of extracellularmatrix proteins in the kidney.

TABLE 2 Hydroxyproline content Administration group (mg/g) Normal mice392.9 ± 10.8   UUO treatment + solvent 549.4 ± 15.2 ### UUO treatment +compound 514.4 ± 20.8   384 (5 mg/kg) UUO treatment + compound 487.7 ±10.9 **  384 (15 mg/kg) UUO treatment + compound 425.7 ± 14.2 *** 384(50 mg/kg) [In the table, ### indicates that p < 0.001 in Student'st-test against the normal mouse group, and ** and *** respectivelyindicate that p < 0.01 and p < 0.001 in Student's t-test against UUOtreatment + solvent group.

Test Example 3 Measurement of Fibrotic Inhibitory Activity Using MouseUnilateral Ureteral Obstruction (UUO) Model

The fibrotic inhibitory activity of a compound according to the presentinvention was evaluated using the same model as used in Test Example 2.Compound 320 prepared in the working example was used as the testcompound.

The experiment method and evaluation method were the same as those inTest Example 2, except that the compound administration was carried outby feeding a diet mixed with the compound for 10 days and the correctionof hydroxyproline content was changed to the content of protein in thekidney extract.

The results were as shown in Table 3. The values in the table areaverage of data on five mice for each group ±standard deviation.

As a result, it was found that, as compared with the solventadministration group, for the group to which the compound according tothe present invention had been administered, the content ofhydroxyproline was significantly lowered, indicating that the compoundaccording to the present invention could suppress the accumulation ofextracellular matrix proteins in the kidney.

TABLE 3 Hydroxyproline content Administration group (mg/g protein)Normal mice 6.7 ± 1.26  UUO treatment + solvent 12.7 ± 1.14 # UUOtreatment + compound 9.44 ± 0.53 * 320 (0.1% mixed diet) UUO treatment +compound 9.19 ± 0.38 * 320 (0.3% mixed diet) [In the table, # indicatesthat p < 0.05 in Student's t-test against the normal mouse group, and **indicates that p < 0.05 in Student's t-test against UUO treatment +solvent group.

Test Example 4 Measurement of Fibrotic Inhibitory Activity Using MouseDMN Hepatic Fibrosis Model

The fibrotic inhibitory activity of a compound according to the presentinvention was evaluated using a mouse DMN hepatic fibrosis model as aliver fibrosis model. Compound 384 prepared in the working example wasused as the test compound.

Six-week-old male BALB/c mice (available from Charles River Japan, Inc.)were purchased and were pre-raised before use in experiments.

The mice were divided into a vehicle administration group (n=6) and atest compound administration group (n=7) using the weight as an index.Thereafter, dimethylnitrosoamine (DMN) diluted with physiological salinewas intraperitoneally administered at 15 mg/kg three times per week for3 weeks to induce hepatic fibrosis.

The administration of the test compound was carried out from the firstday of the DMN administration. The test compound was mixed in amounts of0.015, 0.03, and 0.06% in powder diet CE-2 (available from CLEA JAPANINC.), and the mixtures were fed as a diet to each mouse group.

After 21 days, the mice underwent laparotomy under ether anesthesia, andblood was collected from the heart, followed by measurement of the levelof hyaluronic acid in blood as an index of hepatic fibrosis with ahyaluronic acid plate (Chugai Pharmaceutical Co., Ltd.).

The results were as shown in Table 3. The values in the table areaverage of data on 6 mice for each group ±standard deviation.

As a result, it was found that, as compared with the liver of normalmice, for the mouse liver to which DMN had been administered, thehyaluronic acid level of blood was increased and extracellular matrixproteins accumulated within the liver. As compared with the solventadministration group, for the group to which the compound according tothe present invention had been administered, the hyaluronic acid levelof blood was lowered, indicating that the compound according to thepresent invention could suppress the accumulation of extracellularmatrix proteins in the liver.

TABLE 4 Hyaluronic acid level Administration group of blood (ng/ml)Normal mice 113.8 ± 14.9  DMN administration + solvent  326.4 ± 47.1 ##DMN administration + compound 167.8 ± 25.0 * 384 (0.015% mixed diet) DMNadministration + compound 108.5 ± 9.0 ** 384 (0.03% mixed diet) DMNadministration + compound  97.2 ± 11.0 ** 384 (0.06% mixed diet) [In thetable, ## indicates that p < 0.01 in Student's t-test against the normalmouse group, and * and ** respectively indicate that p < 0.05 and p <0.01 in Student's t-test against UUO treatment + solvent group.

1. A compound represented by formula (I) or a pharmaceuticallyacceptable salt or solvate thereof:

wherein X represents or N, Z represents —O—, —NH—, —S—, or —C(═O)—, Rand R′, which may be the same or different, represent 1) a hydrogenatom, 2) a halogen atom, or 3) C₁₋₆ alkyl optionally substituted byhydroxyl, a halogen atom, or a saturated or unsaturated five- orsix-membered heterocyclic group, 4) C₂₋₆ alkenyl optionally substitutedby an oxygen atom or C₁₋₄ alkoxy, 5) amino in which one or two hydrogenatoms on the amino group are optionally substituted by C₁₋₆ alkyl, andthe C₁₋₆ alkyl group is optionally substituted by hydroxyl or asaturated or unsaturated five- or six-membered carbocyclic orheterocyclic group, 6) —C(═O)—NH₂ wherein one or two hydrogen atoms onthe aminocarbonyl group are optionally substituted by C₁₋₆ alkyl, 7)—OR″ wherein R″ represents a hydrogen atom, or —(CH₂)_(m)—R^(a) whereinR^(a) represents a hydrogen atom, a halogen atom, hydroxyl, a saturatedor unsaturated three- to six-membered carbocyclic or heterocyclic group,C₁₋₄ alkoxy, C₁₋₄ alkoxycarbonyl, or —NR^(b)R^(c) wherein R^(b) andR^(c), which may be the same or different, represent a hydrogen atom orC₁₋₆ alkyl, in which the C₁₋₆ alkyl group is optionally substituted byhydroxyl, an oxygen atom, amino, a nitrogen atom, or C₁₋₄ alkyl, andR^(b) and R^(c) may combine with a nitrogen atom attached thereto toform a saturated or unsaturated five- or six-membered heterocyclicgroup, which may further comprise one or more heteroatoms, and in whichthe heterocyclic group is optionally substituted by C₁₋₄ alkyloptionally substituted by hydroxyl, hydroxyl, an oxygen atom,aminocarbonyl, C₁₋₄ alkoxy, C₁₋₄ alkoxycarbonyl, or a saturated orunsaturated five- or six-membered heterocyclic group, and theheterocyclic group may condense with another saturated or unsaturatedfive- or six-membered carbocyclic or heterocyclic group to form abicyclic group; m is an integer of 1 to 6; and the alkyl chain part inthis group, —(CH₂)_(m)—, is optionally substituted by hydroxyl, anoxygen atom, —OR^(d) group, wherein R^(d) represents C₁₋₄ alkyl or C₁₋₄alkylcarbonyl, or C₁₋₄ alkyl optionally substituted by hydroxyl or ahalogen atom, or 8) a saturated or unsaturated five- or six-memberedheterocyclic group, and A represents any group selected from the groupconsisting of formulae (a) to (c): (a) a group of formula (a):

wherein R³ to R⁶, which may be the same or different, represent ahydrogen atom, hydroxyl, a halogen atom, C₁₋₆ alkyl, C₁₋₁₀ alkoxyoptionally substituted by a halogen atom or phenyl, C₂₋₆alkenylcarbonyloxy, C₁₋₄ alkylcarbonyl, C₁₋₄ alkylthio, or phenyloptionally substituted by a halogen atom, R³ and R⁴, R⁴ and R⁵, and R⁵and R⁶ each may combine with a carbon atom attached thereto to form asaturated or unsaturated five- or six-membered carbocyclic orheterocyclic group in which the carbocyclic or heterocyclic group isoptionally substituted by a hydrogen atom, a halogen atom, hydroxyl, orC₁₋₄ alkyl, G represents —C(═O)—R⁷, —CH₂—N(—R¹¹)R¹², or —C(—R¹³)(═NR¹⁴),wherein R⁷ represents a hydrogen atom, C₁₋₈ alkyl optionally substitutedby C₁₋₄ alkoxy, an oxygen atom, or a saturated or unsaturated five- orsix-membered carbocyclic group, C₂₋₆ alkenyl optionally substituted by asaturated or unsaturated five- or six-membered carbocyclic group, asaturated or unsaturated five- or six-membered carbocyclic group orheterocyclic group in which the carbocyclic or heterocyclic group isoptionally substituted by hydroxyl, C₁₋₄ alkyl, or C₁₋₄ alkoxy, and theC₁₋₄ alkoxy group is optionally substituted by a halogen atom or asaturated or unsaturated five- or six-membered heterocyclic group, group—O—R⁸, or group —N(—R⁹)R¹⁰ wherein R⁸ represents C₁₋₁₀ alkyl optionallysubstituted by a saturated or unsaturated five- or six-memberedcarbocyclic group, C₂₋₈ alkenyl, or a saturated or unsaturated five- orsix-membered carbocyclic group in which the carbocyclic group isoptionally substituted by a halogen atom, R⁹ and R¹⁰, and R¹¹ and R¹²,which may be the same or different, each represent a hydrogen atom, C₁₋₆alkyl, a saturated or unsaturated five- or six-membered carbocyclicgroup in which the carbocyclic group is optionally substituted by ahalogen atom, or naphthyl optionally substituted by a halogen atom, R⁹and R¹⁰, or R¹¹ and R¹² may combine with a nitrogen atom attachedthereto to form a saturated or unsaturated five- or six-memberedheterocyclic group which may further comprise one or more heteroatomsand in which the heterocyclic group is optionally substituted by C₁₋₄alkyl optionally substituted by hydroxyl, or a saturated or unsaturatedfive- or six-membered heterocyclic group, R¹³ represents a hydrogen atomor C₁₋₄ alkyl, R¹⁴ represents a hydrogen atom, hydroxyl, C₁₋₄ alkoxyoptionally substituted by a saturated or unsaturated six-memberedcarbocyclic group, C₂₋₆ alkenyloxy, phenyloxy, or amino optionallysubstituted by a saturated or unsaturated six-membered heterocyclicgroup, (b) a group of formula (b):

wherein any one of J, L, and M represents a nitrogen atom with theremaining two representing a carbon atom, R¹⁵ to R¹⁹, which may be thesame or different, represent a hydrogen atom, a halogen atom, nitro,cyano, C₁₋₆ alkyl in which the alkyl group is optionally substituted byhydroxyl; phenyl; amino optionally substituted by C₁₋₄ alkyl; C₁₋₄alkylcarbonyloxy; or a saturated or unsaturated six-memberedheterocyclic group optionally substituted by C₁₋₄ alkyl, C₁₋₈ alkoxy,C₁₋₄ alkylcarbonyl, C₂₋₆ alkenyl optionally substituted by a saturatedor unsaturated five- or six-membered carbocyclic group, C₂₋₆ alkynyloptionally substituted by C₁₋₄ alkylsilyl, C₁₋₄ alkylthio, a saturatedor unsaturated three- to eight-membered carbocyclic oxy group, asaturated or unsaturated six-membered carbocyclic carbonyl orheterocyclic carbonyl group optionally substituted by C₁₋₄ alkyl, or asaturated or unsaturated three- to eight-membered carbocyclic orheterocyclic group in which the carbocyclic or heterocyclic group isoptionally substituted by hydroxyl; cyano; a halogen atom; C₁₋₄ alkoxy;phenyloxy; C₁₋₄ alkylcarbonyl; amino optionally substituted by C₁₋₄alkyl or C₁₋₄ alkylcarbonyl; aminocarbonyl optionally substituted byC₁₋₄ alkyl; or C₁₋₄ alkyl optionally substituted by hydroxyl or ahalogen atom, R¹⁵ and R¹⁶, R¹⁶ and R¹⁷, R¹⁷ and R¹⁸, and R¹⁸ and R¹⁹each may combine with a carbon atom attached thereto to form a saturatedor unsaturated five- or six-membered carbocyclic or heterocyclic group,and the carbocyclic or heterocyclic group is optionally substituted byC₁₋₄ alkyl, provided that, among R¹⁷ to R¹⁹, those in which J, L, or Mattached thereto is a nitrogen atom are absent, and (c) a group offormula (c): wherein R²⁰ to R²⁴, which may be the same or different,represent a hydrogen atom, a halogen atom, C₁₋₁₀ alkyl optionallysubstituted by hydroxyl, a saturated or unsaturated five- orsix-membered carbocyclic or heterocyclic group, C₁₋₈ alkoxy, C₂₋₆alkenyl optionally substituted by C₁₋₄ alkyl, C₁₋₄ alkoxy, an oxygenatom or phenyl, phenylcarbonyl optionally substituted by C₁₋₄ alkyl,amino optionally substituted by phenyl, nitro, or a saturated orunsaturated five- or six-membered carbocyclic or heterocyclic group inwhich the carbocyclic or heterocyclic group is optionally substituted byC₁₋₆ alkyl, R²⁰ and R²¹, or R²³ and R²⁴ may combine with a carbon atomattached thereto to form a saturated or unsaturated five- orsix-membered carbocyclic or heterocyclic group, and R²¹ and R²², or R²²and R²³ may combine with a carbon atom attached thereto to form asaturated or unsaturated five- or six-membered carbocyclic orheterocyclic group in which the carbocyclic or heterocyclic group isoptionally substituted by a halogen atom, C₁₋₄ alkyl, C₁₋₄alkylcarbonyl, C₁₋₆ alkoxycarbonyl, or an oxygen atom, and thecarbocyclic or heterocyclic group may condense with another saturated orunsaturated five- or six-membered carbocyclic or heterocyclic group toform a tricyclic group together with the six-membered carbocyclic ringof formula (c).
 2. The compound according to claim 1, represented byformula (II), or a pharmaceutically acceptable salt or solvate thereof:

wherein X, Z, and A are as defined in claim 1, R¹ and R², which may bethe same or different, represent a hydrogen atom, or —(CH₂)_(m)—R^(a)wherein R^(a) represents a hydrogen atom, a halogen atom, hydroxyl, asaturated or unsaturated three- to six-membered carbocyclic orheterocyclic group, C₁₋₄ alkoxy, C₁₋₄ alkoxycarbonyl, or —NR^(b)R^(c)wherein R^(b) and R^(c), which may be the same or different, represent ahydrogen atom or C₁₋₆ alkyl, in which the C₁₋₆ alkyl group is optionallysubstituted by hydroxyl, an oxygen atom, amino, a nitrogen atom, or C₁₋₄alkyl, and R^(b) and R^(c) may combine with a nitrogen atom attachedthereto to form a saturated or unsaturated five- or six-memberedheterocyclic group, which may further comprise one or more heteroatoms,and in which the heterocyclic group is optionally substituted by C₁₋₄alkyl, optionally substituted by hydroxyl, hydroxyl, an oxygen atom,aminocarbonyl, C₁₋₄ alkoxy, C₁₋₄ alkoxycarbonyl, or a saturated orunsaturated five- or six-membered heterocyclic group, and theheterocyclic group may condense with another saturated or unsaturatedfive- or six-membered carbocyclic or heterocyclic group to form abicyclic group; m is an integer of 1 to 6; and the alkyl chain part inthis group, —(CH₂)_(m)—, is optionally substituted by hydroxyl, anoxygen atom, —OR^(d) group, wherein R^(d) represents C₁₋₄ alkyl or C₁₋₄alkylcarbonyl, or C₁₋₄ alkyl optionally substituted by hydroxyl or ahalogen atom.
 3. The compound according to claim 2, wherein R¹ and R²,which may be the same or different, represent any group selected fromthe group consisting of a hydrogen atom, C₁₋₆ alkyl optionallysubstituted by phenyl, and groups of formulae (i) to (vi): (i) a groupof formula (i):

wherein R⁵¹ and R⁵², which may be the same or different, represent ahydrogen atom, or C₁₋₈ alkyl optionally substituted by hydroxyl, anoxygen atom, amino, or a nitrogen atom, R⁵¹ and R⁵² may combine with anitrogen atom attached thereto to form a saturated or unsaturated five-or six-membered heterocyclic group which may further comprise one ormore heteroatoms, and in which the heterocyclic group is optionallysubstituted by C₁₋₄ alkyl optionally substituted by hydroxyl, hydroxyl,an oxygen atom, aminocarbonyl, C₁₋₄ alkoxy, C₁₋₄ alkoxycarbonyl, or asaturated or unsaturated five- or six-membered heterocyclic group, andthe heterocyclic group optionally formed by allowing R⁵¹ to combine withR⁵² may condense with another saturated or unsaturated five- orsix-membered carbocyclic or heterocyclic group to form a bicyclic group,p is an integer of 2 to 4, and the alkyl chain part in this group isoptionally substituted by hydroxyl, or —OR^(e) group wherein R^(e)represents C₁₋₄ alkyl or C₁₋₄ alkylcarbonyl, (ii) a group of formula(ii):

wherein q is an integer of 1 to 4, (iii) a group of formula (iii):

wherein Hal represents a halogen atom, and r represents an integer of 2to 4, (iv) a group of formula (iv):

wherein R⁵³ and R⁵⁴, which may be the same or different, represent ahydrogen atom, or C₁₋₆ alkyl optionally substituted by hydroxyl, R⁵³ andR⁵⁴ may combine with a nitrogen atom attached thereto to form asaturated or unsaturated five- or six-membered heterocyclic group whichmay further comprise one or more heteroatoms and in which theheterocyclic group is optionally substituted by C₁₋₄ alkyl optionallysubstituted by hydroxyl, or a saturated or unsaturated five- orsix-membered heterocyclic group, and the heterocyclic group optionallyformed by allowing R⁵³ to combine with R⁵⁴ may condense with anothersaturated or unsaturated five- or six-membered carbocyclic orheterocyclic group to form a bicyclic group, and s is an integer of 0 to3, (v) a group of formula (v):

wherein R⁵⁵ represents C₁₋₄ alkyl and t is an integer of 0 (zero) to 3,and (vi) a group of formula (vi):

wherein R⁵⁶, R⁵⁷ and R⁵⁸, which may be the same or different, representa hydrogen atom, C₁₋₄ alkoxycarbonyl, or C₁₋₄ alkyl optionallysubstituted by hydroxyl or a halogen atom, and u is an integer of 0(zero) to
 4. 4. The compound according to claim 3, wherein formula (i)is represented by formula (i-a):


5. The compound according to claim 3 or 4, wherein R¹ and R², which maybe the same or different, represent any group selected from the groupconsisting of a hydrogen atom, C₁₋₆ alkyl, benzyl, groups of formulae(i), (v), and (vi) according to claim 3, and groups of formulae (ii-a),(iii-a), and (iv-a): formula (ii-a):

formula (iii-a):

wherein r1 is an integer of 2 to 4, and formula (iv-a):


6. The compound according to claim 5, wherein one of R¹ and R² isselected from C₁₋₆ alkyl, and the other substituent is selected from thegroup consisting of a hydrogen atom, benzyl, groups of formulae (i),(v), and (vi) according to claim 3, and groups of formulae (ii-a),(iii-a), and (iv-a) according to claim
 5. 7. The compound according toclaim 1, wherein at least one of R and R′ is selected from the groupconsisting of a hydrogen atom, a halogen atom, C₁₋₄ alkyl optionallysubstituted by hydroxyl, a halogen atom, or a saturated or unsaturatedfive- or six-membered heterocyclic group, C₂₋₄ alkenyl optionallysubstituted by an oxygen atom or C₁₋₄ alkoxy, amino in which one or twohydrogen atoms on the amino group are optionally substituted by C₁₋₄alkyl, and the C₁₋₄ alkyl group is optionally substituted by hydroxyl ora saturated or unsaturated five- or six-membered heterocyclic group,—C(═O)—NH₂, and a saturated or unsaturated five- or six-memberedheterocyclic group.
 8. The compound according to claim 1, wherein R′ isselected from the group consisting of a hydrogen atom, a halogen atom,C₁₋₄ alkyl optionally substituted by hydroxyl, a halogen atom, or asaturated or unsaturated five- or six-membered heterocyclic group, C₂₋₄alkenyl optionally substituted by an oxygen atom or C₁₋₄ alkoxy, aminoin which one or two hydrogen atoms on the amino group are optionallysubstituted by C₁₋₄ alkyl, and the C₁₋₄ alkyl group is optionallysubstituted by hydroxyl or a saturated or unsaturated five- orsix-membered heterocyclic group, —C(═O)—NH₂, and a saturated orunsaturated five- or six-membered heterocyclic group.
 9. The compoundaccording to claim 1, wherein formula (a), which A may represent,represents any group selected from the group consisting of formulae (a1)to (a3): (1) a group of formula (a1):

wherein R³, R⁴ and R⁶, which may be the same or different, represent ahydrogen atom, a halogen atom, C₁₋₆ alkyl, C₁₋₁₀ alkoxy optionallysubstituted by a halogen atom or phenyl, C₂₋₆ alkenylcarbonyloxy, C₁₋₄alkylcarbonyl, or phenyl optionally substituted by a halogen atom, R⁵ isas defined in claim 1, R³ and R⁴, R⁴ and R⁵, and R⁵ and R⁶ each maycombine with a carbon atom attached thereto to form a saturated orunsaturated five- or six-membered carbocyclic or heterocyclic group, andR⁷ is as defined in claim 1, (2) a group of formula (a2):

wherein R³ to R⁶ are as defined in formula (a1), R¹¹ and R¹² are asdefined in claim 1, and (3) a group of formula (a3):

wherein R^(3a) to R^(6a), which may be the same or different, representa hydrogen atom, a halogen atom, or C₁₋₆ alkyl, and R¹³ and R¹⁴ are asdefined in claim
 1. 10. The compound according to claim 9, wherein Arepresents a group of formula (a1) and at least one of R³ to R⁶ informula (a1) is selected from groups other than a hydrogen atom.
 11. Thecompound according to claim 9 or 10, wherein A represents a group offormula (a1) and R⁷ in formula (a1) represents a hydrogen atom, C₁₋₄alkyl, or phenyl in which the phenyl group is optionally substituted byhydroxyl, C₁₋₄ alkyl, or C₁₋₄ alkoxy.
 12. The compound according toclaim 9 or 10, wherein A represents a group of formula (a1) and R⁷ informula (a1) represents group —O—R⁸ or group —N(—R⁹)R¹⁰.
 13. Thecompound according to claim 12, wherein R⁸ represents unsubstituted C₁₋₈alkyl; C₁₋₄ alkyl substituted by phenyl; C₂₋₈ alkenyl; or phenyloptionally substituted by a halogen atom.
 14. The compound according toclaim 12, wherein at least one of R⁹ and R¹⁰ represents a hydrogen atomand the other substituent represents a hydrogen atom, C₁₋₆ alkyl, asaturated or unsaturated five- or six-membered carbocyclic group inwhich the carbocyclic group is optionally substituted by a halogen atom,or naphthyl optionally substituted by a halogen atom, or R⁹ and R¹⁰combine with a nitrogen atom attached thereto to form a saturated five-or six-membered heterocyclic group in which the heterocyclic group mayfurther comprise at least one heteroatom.
 15. The compound according toclaim 9, wherein A represents a group of formula (a1) and R⁵ in formula(a1) is selected from groups other than a hydrogen atom.
 16. Thecompound according to claim 10, wherein R and R′ are selected from —OR″wherein R″ represents C₁₋₆ alkyl.
 17. The compound according to claim 9,wherein A represents a group of formula (a2) and R¹¹ and R¹² in formula(a2) combine with a nitrogen atom attached thereto to form a saturatedor unsaturated five- or six-membered heterocyclic group in which theheterocyclic group may further comprise one or more heteroatoms and isoptionally substituted by C₁₋₄ alkyl optionally substituted by hydroxyl;or a saturated five- or six-membered heterocyclic group.
 18. Thecompound according to claim 17, wherein A represents a group of formula(a2) and, in formula (a2), R³, R⁴, and R⁶ represent a hydrogen atom,hydroxyl, or a halogen atom, and R⁵ represents C₁₋₄ alkyl.
 19. Thecompound according to claim 9, wherein A represents a group of formula(a3) and, in formula (a3), R¹³ represents methyl, and R¹⁴ representshydroxyl; C₁₋₄ alkoxy optionally substituted by phenyl; C₂₋₆ alkenyloxy;phenyloxy; or amino optionally substituted by a six-membered unsaturatedheterocyclic group.
 20. The compound according to claim 9 or 19, whereinA represents a group of formula (a3), and, in formula (a3), R^(3a) andR^(6a) represents a hydrogen atom, and R^(4a) and R^(5a) represent C₁₋₆alkyl.
 21. The compound according to claim 1, wherein A is selected fromgroups of formula (a) or (b).
 22. The compound according to claim 1,wherein formula (b), which A may represent, represents any groupselected from the group consisting of formulae (b1) to (b3): (4) a groupof formula (b1):

wherein R²⁵ to R²⁷, which may be the same or different, represent ahydrogen atom, a halogen atom, C₁₋₆ alkyl, C₁₋₈ alkoxy, C₁₋₄alkylcarbonyl, C₁₋₄ alkylthio, or phenylcarbonyl, R²⁵ and R²⁶, and R²⁶and R²⁷ each may combine with a carbon atom attached thereto to form asaturated or unsaturated five- or six-membered carbocyclic orheterocyclic group, R²⁸ represents a hydrogen atom, a halogen atom,nitro, cyano, C₁₋₆ alkyl in which the alkyl group is optionallysubstituted by hydroxyl; phenyl; amino optionally substituted by C₁₋₄alkyl; C₁₋₄ alkylcarbonyloxy; or a saturated or unsaturated six-memberedheterocyclic group optionally substituted by C₁₋₄ alkyl, C₁₋₈ alkoxy,C₁₋₄ alkylcarbonyl, C₂₋₆ alkenyl optionally substituted by a saturatedor unsaturated six-membered carbocyclic group, C₂₋₆ alkynyl optionallysubstituted by C₁₋₂ alkylsilyl, a saturated or unsaturated three- toeight-membered carbocyclic oxy group, a saturated or unsaturatedsix-membered carbocyclic carbonyl or heterocyclic carbonyl groupoptionally substituted by C₁₋₄ alkyl, or a saturated or unsaturatedthree- to eight-membered carbocyclic or heterocyclic group in which thecarbocyclic or heterocyclic group is optionally substituted by hydroxyl;cyano; a halogen atom; C₁₋₄ alkoxy; phenyloxy; C₁₋₄ alkylcarbonyl; aminooptionally substituted by C₁₋₄ alkyl or C₁₋₄ alkylcarbonyl;aminocarbonyl optionally substituted by C₁₋₄ alkyl; or C₁₋₄ alkyloptionally substituted by hydroxyl or a halogen atom, (5) a group offormula (b2):

wherein R²⁹ to R³², which may be the same or different, represent ahydrogen atom, a halogen atom, or C₁₋₆ alkyl optionally substituted byhydroxyl, R²⁹ and R³⁰, and R³¹ and R³² each may combine with a carbonatom attached thereto to form a saturated or unsaturated five- orsix-membered carbocyclic or heterocyclic group in which the carbocyclicor heterocyclic group is optionally substituted by a halogen atom orC₁₋₄ alkyl, and (6) a group of formula (b3):

wherein R³³ to R³⁶, which may be the same or different, represent ahydrogen atom, a halogen atom, or C₁₋₆ alkyl optionally substituted byhydroxyl, R³³ and R³⁴, R³⁴ and R³⁵, and R³⁵ and R³⁶ each may combinewith a carbon atom attached thereto to form a saturated or unsaturatedfive- or six-membered carbocyclic or heterocyclic group in which thecarbocyclic or heterocyclic group is optionally substituted by a halogenatom or C₁₋₄ alkyl.
 23. The compound according to claim 22, wherein Arepresents a group of formula (b1) and, in formula (b1), R²⁵ representsa hydrogen atom, R²⁶ represents a hydrogen atom, a halogen atom, or C₁₋₄alkyl, R²⁷ represents a hydrogen atom, a halogen atom, C₁₋₄ alkyl, C₁₋₄alkoxy, or C₁₋₄ alkylthio, and R²⁶ and R²⁷ may combine with a carbonatom attached thereto to form an unsaturated six-membered carbocyclic orheterocyclic group.
 24. The compound according to claim 1, wherein Arepresents a group of formula (b1) and, in formula (b1), R²⁵ representsa hydrogen atom, R²⁶ represents a hydrogen atom, a halogen atom, or C₁₋₄alkyl, R²⁷ represents a hydrogen atom, a halogen atom, C₁₋₄ alkyl, C₁₋₄alkoxy, or C₁₋₄ alkylthio, R²⁶ and R²⁷ may combine with a carbon atomattached thereto to form an unsaturated six-membered carbocyclic orheterocyclic group, and R²⁸ represents a saturated or unsaturated four-to seven-membered carbocyclic or heterocyclic group in which thecarbocyclic or heterocyclic group is optionally substituted by hydroxyl;cyano; a halogen atom; C₁₋₄ alkoxy; phenyloxy; C₁₋₄ alkylcarbonyl; aminooptionally substituted by C₁₋₄ alkyl or C₁₋₄ alkylcarbonyl;aminocarbonyl optionally substituted by C₁₋₄ alkyl; or C₁₋₄ alkyloptionally substituted by hydroxyl or a halogen atom.
 25. The compoundaccording to claim 22, wherein A represents a group of formula (b2) and,in formula (b2), R²⁹ represents a hydrogen atom, R³⁰ represents ahydrogen atom or C₁₋₄ alkyl, and R³¹ and R³² combine with carbon atomattached thereto to from an unsaturated five- or six-memberedcarbocyclic or heterocyclic group in which the carbocyclic orheterocyclic group is optionally substituted by a halogen atom or C₁₋₄alkyl.
 26. The compound according to claim 22, wherein A represents agroup of formula (b3) and, in formula (b3), R³³ and R³⁴ represent ahydrogen atom, and R³⁵ and R³⁶ combine with a carbon atom attachedthereto to form an unsaturated five- or six-membered carbocyclic orheterocyclic group.
 27. The compound according to claim 1, wherein whenone of R¹ and R² is selected from C₁₋₆ alkyl, and the other substituentis selected from the group consisting of a hydrogen atom, benzyl, groupsof formulae (i), (v), and (vi) according to claim 3, and groups offormulae (ii-a), (iii-a), and (iv-a) according to claim 5, A is selectedfrom groups of formula (b1).
 28. The compound according to claim 1,wherein A represents a group of formula (c) and, in formula (c), R²¹ andR²², or R²² and R²³ combine with a carbon atom attached thereto to forma saturated or unsaturated five- or six-membered carbocyclic orheterocyclic group in which the carbocyclic or heterocyclic group isoptionally substituted by a halogen atom, C₁₋₄ alkyl, C₁₋₄alkylcarbonyl, C₁₋₆ alkoxycarbonyl, or an oxygen atom and may condensewith another saturated or unsaturated five- or six-membered carbocyclicor heterocyclic group to form, together with the six-memberedcarbocyclic ring in formula (c), a tricyclic group, and any one of orboth R²⁰ and R²⁴ is selected from groups other than a hydrogen atom. 29.The compound according to claim 1 or pharmaceutically acceptable salt orsolvate thereof, wherein formula (I) is represented by formula (100):

wherein X represents CH or N, Z represents —O—, —NH—, —S—, or —C(═O)—,R¹⁰¹ and R¹⁰², which may be the same or different, represent any groupselected from the group consisting of a hydrogen atom, C₁₋₆ alkyl,benzyl, and groups of formulae (i), (ii-a), (iii-a), (iv-a), (v), and(vi), (i) a group of formula (i):

wherein R⁵¹ and R⁵², which may be the same or different, represent ahydrogen atom, or C₁₋₈ alkyl optionally substituted by hydroxyl, anoxygen atom, amino, or a nitrogen atom, R⁵¹ and R⁵² may combine with anitrogen atom attached thereto to form a saturated or unsaturated five-or six-membered heterocyclic group which may further comprise one ormore heteroatoms and in which the heterocyclic group is optionallysubstituted by C₁₋₄ alkyl, optionally substituted by hydroxyl, hydroxyl,an oxygen atom, aminocarbonyl, C₁₋₄ alkoxy, C₁₋₄ alkoxycarbonyl, or asaturated or unsaturated five- or six-membered heterocyclic group, andthe heterocyclic group optionally formed by allowing R⁵¹ to combine withR⁵² may condense with another saturated or unsaturated five- orsix-membered carbocyclic or heterocyclic group to form a bicyclic group,p is an integer of 2 to 4, and the alkyl chain part in this group isoptionally substituted by hydroxyl, or —OR^(e) group wherein R^(e)represents C₁₋₄ alkyl or C₁₋₄ alkylcarbonyl, (ii) a group of formula(ii-a):

(iii) a group of formula (iii-a):

wherein r1 represents an integer of 2 to 4, (iv) a group of formula(iv-a):

wherein R⁵³ and R⁵⁴, which may be the same or different, represent ahydrogen atom, or C₁₋₆ alkyl optionally substituted by hydroxyl, and R⁵³and R⁵⁴ may combine with a nitrogen atom attached thereto to form asaturated or unsaturated five- or six-membered heterocyclic group whichmay further comprise one or more heteroatoms and in which theheterocyclic group is optionally substituted by C₁₋₄ alkyl, optionallysubstituted by hydroxyl, or a saturated or unsaturated five- orsix-membered heterocyclic group, and the heterocyclic group optionallyformed by allowing R⁵³ to combine with R⁵⁴ may condense with anothersaturated or unsaturated five- or six-membered carbocyclic orheterocyclic group to form a bicyclic group, (v) a group of formula (v):

wherein R⁵⁵ represents C₁₋₄ alkyl and t is an integer of 0 (zero) to 3,and (vi) a group of formula (vi):

wherein R⁵⁶, R⁵⁷ and R⁵⁸, which may be the same or different, representa hydrogen atom, C₁₋₄ alkoxycarbonyl, or C₁₋₄ alkyl optionallysubstituted by hydroxyl or a halogen atom, and u is an integer of 0(zero) to 4, R¹⁰³, R¹⁰⁴ and R¹⁰⁶, which may be the same or different,represent a hydrogen atom, a halogen atom, C₁₋₆ alkyl, C₁₋₁₀ alkoxyoptionally substituted by a halogen atom or phenyl, C₂₋₆alkenylcarbonyloxy, C₁₋₄ alkylcarbonyl, or phenyl optionally substitutedby a halogen atom, R¹⁰⁵ represents hydroxyl, a halogen atom, C₁₋₆ alkyl,C₁₋₁₀ alkoxy optionally substituted by a halogen atom or phenyl, C₂₋₆alkenylcarbonyloxy, C₁₋₄ alkylcarbonyl, C₁₋₄ alkylthio, or phenyloptionally substituted by a halogen atom, R¹⁰³ and R¹⁰⁴, R¹⁰⁴ and R¹⁰⁵,and R¹⁰⁵ and R¹⁰⁶ each may combine with a carbon atom attached theretoto form a saturated or unsaturated five- or six-membered carbocyclic orheterocyclic group, R¹⁰⁷ represents a hydrogen atom, C₁₋₄ alkyl, orphenyl optionally substituted by hydroxyl, C₁₋₄ alkyl, or C₁₋₄ alkoxy.30. The compound according to claim 29, wherein Z represents —O—, atleast one of R¹⁰¹ and R¹⁰² represents methyl, and R¹⁰⁷ represents ahydrogen atom, methyl, ethyl, or phenyl optionally substituted byhydroxyl, C₁₋₄ alkyl or C₁₋₄ alkoxy.
 31. The compound according to claim1 or pharmaceutically acceptable salt or solvate thereof, whereinformula (I) is represented by formula (200):

wherein X represents CH or N, Z represents —O—, —NH—, —S—, or —C(═O)—,R²⁰¹ and R²⁰², which may be the same or different, represent any groupselected from the group consisting of a hydrogen atom, C₁₋₆ alkyl,benzyl, and groups of formulae (i), (ii-a), (iii-a), (iv-a), (v), and(vi), (i) a group of formula (i):

wherein R⁵¹ and R⁵², which may be the same or different, represent ahydrogen atom, or C₁₋₈ alkyl optionally substituted by hydroxyl, anoxygen atom, amino, or a nitrogen atom, R⁵¹ and R⁵² may combine with anitrogen atom attached thereto to form a saturated or unsaturated five-or six-membered heterocyclic group which may further comprise one ormore heteroatoms and in which the heterocyclic group is optionallysubstituted by C₁₋₄ alkyl, optionally substituted by hydroxyl, hydroxyl,an oxygen atom, aminocarbonyl, C₁₋₄ alkoxy, C₁₋₄ alkoxycarbonyl, or asaturated or unsaturated five- or six-membered heterocyclic group, andthe heterocyclic group optionally formed by allowing R⁵¹ to combine withR⁵² may condense with another saturated or unsaturated five- orsix-membered carbocyclic or heterocyclic group to form a bicyclic group,p is an integer of 2 to 4, and the alkyl chain part in this group isoptionally substituted by hydroxyl, or —OR^(e) group wherein R^(e)represents C₁₋₄ alkyl or C₁₋₄ alkylcarbonyl, (ii) a group of formula(ii-a):

(iii) a group of formula (iii-a):

wherein r1 represents an integer of 2 to 4, (iv) a group of formula(iv-a):

wherein R⁵³ and R⁵⁴, which may be the same or different, represent ahydrogen atom, or C₁₋₆ alkyl optionally substituted by hydroxyl, and R⁵³and R⁵⁴ may combine with a nitrogen atom attached thereto to form asaturated or unsaturated five- or six-membered heterocyclic group whichmay further comprise one or more heteroatoms and in which theheterocyclic group is optionally substituted by C₁₋₄ alkyl, optionallysubstituted by hydroxyl, or a saturated or unsaturated five- orsix-membered heterocyclic group, and the heterocyclic group optionallyformed by allowing R⁵³ to combine with R⁵⁴ may condense with anothersaturated or unsaturated five- or six-membered carbocyclic orheterocyclic group to form a bicyclic group, (v) a group of formula (v):

wherein R⁵⁵ represents C₁₋₄ alkyl and t is an integer of 0 (zero) to 3,and (vi) a group of formula (vi):

wherein R⁵⁶, R⁵⁷ and R⁵⁸, which may be the same or different, representa hydrogen atom, C₁₋₄ alkoxycarbonyl, or C₁₋₄ alkyl optionallysubstituted by hydroxyl or a halogen atom, and u is an integer of 0(zero) to 4, R²⁰³ to R²⁰⁶, which may be the same or different, representa hydrogen atom, hydroxyl, a halogen atom, C₁₋₆ alkyl, C₁₋₁₀ alkoxyoptionally substituted by a halogen atom or phenyl, C₂₋₆alkenylcarbonyloxy, C₁₋₄ alkylcarbonyl, C₁₋₄ alkylthio, or phenyloptionally substituted by a halogen atom, R²⁰³ and R²⁰⁴, R²⁰⁴ and R²⁰⁵,and R²⁰⁵ and R²⁰⁶ each may combine with a carbon atom attached theretoto form a saturated or unsaturated five- or six-membered carbocyclic orheterocyclic group, provided that at least one of R²⁰³ to R²⁰⁶ isselected from a group other than a hydrogen atom, and R²⁰⁸ representsunsubstituted C₁₋₈ alkyl; C₁₋₄ alkyl substituted by phenyl; C₂₋₈alkenyl; or phenyl optionally substituted by a halogen atom.
 32. Thecompound according to claim 31, wherein Z represents —O—, S—, or—C(═O)—, and R²⁰⁸ represents unsubstituted C₁₋₈ alkyl; methylsubstituted by phenyl; C₂₋₈ alkenyl; or phenyl.
 33. The compoundaccording to claim 1 or pharmaceutically acceptable salt or solvatethereof, wherein formula (I) is represented by formula (300):

wherein X represents CH or N, Z represents —O—, —NH—, —S—, or —C(═O)—,R³⁰¹ and R³⁰², which may be the same or different, represent any groupselected from the group consisting of a hydrogen atom, C₁₋₆ alkyl,benzyl, and groups of formulae (i), (ii-a), (iii-a), (iv-a), (v), and(vi), (i) a group of formula (i):

wherein R⁵¹ and R⁵², which may be the same or different, represent ahydrogen atom, or C₁₋₈ alkyl optionally substituted by hydroxyl, anoxygen atom, amino, or a nitrogen atom, R⁵¹ and R⁵² may combine with anitrogen atom attached thereto to form a saturated or unsaturated five-or six-membered heterocyclic group which may further comprise one ormore heteroatoms and in which the heterocyclic group is optionallysubstituted by C₁₋₄ alkyl, optionally substituted by hydroxyl, hydroxyl,an oxygen atom, aminocarbonyl, C₁₋₄ alkoxy, C₁₋₄ alkoxycarbonyl, or asaturated or unsaturated five- or six-membered heterocyclic group, andthe heterocyclic group optionally formed by allowing R⁵¹ to combine withR⁵² may condense with another saturated or unsaturated five- orsix-membered carbocyclic or heterocyclic group to form a bicyclic group,p is an integer of 2 to 4, and the alkyl chain part in this group isoptionally substituted by hydroxyl, or —OR^(e) group wherein R^(e)represents C₁₋₄ alkyl or C₁₋₄ alkylcarbonyl, (ii) a group of formula(ii-a):

(iii) a group of formula (iii-a):

wherein r1 represents an integer of 2 to 4, (iv) a group of formula(iv-a):

wherein R⁵³ and R⁵⁴, which may be the same or different, represent ahydrogen atom, or C₁₋₆ alkyl optionally substituted by hydroxyl, and R⁵³and R⁵⁴ may combine with a nitrogen atom attached thereto to form asaturated or unsaturated five- or six-membered heterocyclic group whichmay further comprise one or more heteroatoms and in which theheterocyclic group is optionally substituted by C₁₋₄ alkyl, optionallysubstituted by hydroxyl, or a saturated or unsaturated five- orsix-membered heterocyclic group, and the heterocyclic group optionallyformed by allowing R⁵³ to combine with R⁵⁴ may condense with anothersaturated or unsaturated five- or six-membered carbocyclic orheterocyclic group to form a bicyclic group, (v) a group of formula (v):

wherein R⁵⁵ represents C₁₋₄ alkyl and t is an integer of 0 (zero) to 3,and (vi) a group of formula (vi):

wherein R⁵⁶, R⁵⁷ and R⁵⁸, which may be the same or different, representa hydrogen atom, C₁₋₄ alkoxycarbonyl, or C₁₋₄ alkyl optionallysubstituted by hydroxyl or a halogen atom, and u is an integer of 0(zero) to 4, R³⁰³ to R³⁰⁶, which may be the same or different, representa hydrogen atom, hydroxyl, a halogen atom, C₁₋₆ alkyl, C₁₋₁₀ alkoxyoptionally substituted by a halogen atom or phenyl, C₂₋₆alkenylcarbonyloxy, C₁₋₄ alkylcarbonyl, C₁₋₄ alkylthio, or phenyloptionally substituted by a halogen atom, R³⁰³ and R³⁰⁴, R³⁰⁴ and R³⁰⁵,and R³⁰⁵ and R³⁰⁶ each may combine with a carbon atom attached theretoto form a saturated or unsaturated five- or six-membered carbocyclic orheterocyclic group, provided that at least one of R³⁰³ to R³⁰⁶ isselected from a group other than a hydrogen atom, and at least one ofR³⁰⁹ and R³¹⁰ represents a hydrogen atom and the other substituentrepresents a hydrogen atom, C₁₋₆ alkyl, a saturated or unsaturated five-or six-membered carbocyclic group in which the carbocyclic group isoptionally substituted by a halogen atom, or naphthyl optionallysubstituted by a halogen atom, or R³⁰⁹ and R³¹⁰ combine with a nitrogenatom attached thereto to form a saturated five- or six-memberedheterocyclic group which may further comprise one or more heteroatoms.34. The compound according to claim 33, wherein Z represents —O—, atleast one of R³⁰⁹ and R³¹⁰ represents a hydrogen atom and the othersubstituent represents a hydrogen atom, C₁₋₄ alkyl, a saturated orunsaturated six-membered carbocyclic group in which the carbocyclicgroup is optionally substituted by a halogen atom, or naphthyl, or R³⁰⁹and R³¹⁰ combine with a nitrogen atom attached thereto to form asaturated six-membered heterocyclic group which may further comprise oneor more heteroatoms.
 35. The compound according to claim 1 orpharmaceutically acceptable salt or solvate thereof, wherein formula (I)is represented by formula (400):

wherein X represents CH or N, Z represents —O—, —NH—, —S—, or —C(═O)—,R⁴⁰¹ and R⁴⁰², which may be the same or different, represent any groupselected from C₁₋₆ alkyl, R⁴⁰³, R⁴⁰⁴, and R⁴⁰⁶ represent a hydrogenatom, hydroxyl, or a halogen atom, R⁴⁰⁵ represents C₁₋₄ alkyl, R⁴¹¹ andR⁴¹² combine with a nitrogen atom attached thereto to form a saturatedor unsaturated five- or six-membered heterocyclic group in which theheterocyclic group may further comprise one or more heteroatoms and isoptionally substituted by C₁₋₄ alkyl optionally substituted by hydroxyl;or a saturated five- or six-membered heterocyclic group.
 36. Thecompound according to claim 35, wherein Z represents —O—, R⁴⁰¹ and R⁴⁰²represent methyl, R⁴¹¹ and R⁴¹² combine with a nitrogen atom attachedthereto to form a saturated five- or six-membered heterocyclic group inwhich the heterocyclic group may further comprise one or moreheteroatoms.
 37. The compound according to claim 1 or pharmaceuticallyacceptable salt or solvate thereof, wherein formula (I) is representedby formula (500):

wherein X represents CH or N, Z represents —O—, —NH—, —S—, or —C(═O)—,R⁵⁰¹ and R⁵⁰², which may be the same or different, represent any groupselected from C₁₋₆ alkyl, R⁵⁰³ and R⁵⁰⁶ represent a hydrogen atom, R⁵⁰⁴and R⁵⁰⁵ represent C₁₋₆ alkyl, and R⁵¹³ represents C₁₋₄ alkyl, and R⁵¹⁴represents hydroxyl; C₁₋₄ alkoxy optionally substituted by phenyl; C₂₋₆alkenyloxy; phenyloxy; or amino optionally substituted by a six-memberedunsaturated heterocyclic group.
 38. The compound according to claim 37,wherein Z represents —O—, R⁵⁰¹ and R⁵⁰² represent methyl, R⁵⁰³ and R⁵⁰⁶represent a hydrogen atom, R⁵⁰⁴ and R⁵⁰⁵ represent methyl, and R⁵¹³represents methyl.
 39. The compound according to claim 1 orpharmaceutically acceptable salt or solvate thereof, wherein formula (I)is represented by formula (600):

wherein X represents or N, Z represents —O—, —NH—, or —S—, or —C(═O)—,R⁶⁰¹ and R⁶⁰², which may be the same or different, represent any groupselected from the group consisting of a hydrogen atom, C₁₋₆ alkyl,benzyl, and groups of formulae (i), (ii-a), (iii-a), (iv-a), (v), and(vi), (i) a group of formula (i):

wherein R⁵¹ and R⁵², which may be the same or different, represent ahydrogen atom, or C₁₋₈ alkyl optionally substituted by hydroxyl, anoxygen atom, amino, or a nitrogen atom, R⁵¹ and R⁵² may combine with anitrogen atom attached thereto to form a saturated or unsaturated five-or six-membered heterocyclic group which may further comprise one ormore heteroatoms and in which the heterocyclic group is optionallysubstituted by C₁₋₄ alkyl, optionally substituted by hydroxyl, hydroxyl,an oxygen atom, aminocarbonyl, C₁₋₄ alkoxy, C₁₋₄ alkoxycarbonyl, or asaturated or unsaturated five- or six-membered heterocyclic group, andthe heterocyclic group optionally formed by allowing R⁵¹ to combine withR⁵² may condense with another saturated or unsaturated five- orsix-membered carbocyclic or heterocyclic group to form a bicyclic group,p is an integer of 2 to 4, and the alkyl chain part in this group isoptionally substituted by hydroxyl, or —OR^(e) group wherein R^(e)represents C₁₋₄ alkyl or C₁₋₄ alkylcarbonyl, (ii) a group of formula(ii-a):

(iii) a group of formula (iii-a):

wherein r1 represents an integer of 2 to 4, (iv) a group of formula(iv-a):

wherein R⁵³ and R⁵⁴, which may be the same or different, represent ahydrogen atom, or C₁₋₆ alkyl optionally substituted by hydroxyl, and R⁵³and R⁵⁴ may combine with a nitrogen atom attached thereto to form asaturated or unsaturated five- or six-membered heterocyclic group whichmay further comprise one or more heteroatoms and in which theheterocyclic group is optionally substituted by C₁₋₄ alkyl, optionallysubstituted by hydroxyl, or a saturated or unsaturated five- orsix-membered heterocyclic group, and the heterocyclic group optionallyformed by allowing R⁵³ to combine with R⁵⁴ may condense with anothersaturated or unsaturated five- or six-membered carbocyclic orheterocyclic group to form a bicyclic group, (v) a group of formula (v):

wherein R⁵⁵ represents C₁₋₄ alkyl and t is an integer of 0 (zero) to 3,and (vi) a group of formula (vi):

wherein R⁵⁶, R⁵⁷ and R⁵⁸, which may be the same or different, representa hydrogen atom, C₁₋₄ alkoxycarbonyl, or C₁₋₄ alkyl optionallysubstituted by hydroxyl or a halogen atom, and u is an integer of 0(zero) to 4, R⁶²⁵ represents a hydrogen atom, R⁶²⁶ represents a hydrogenatom, a halogen atom, or C₁₋₄ alkyl, R⁶²⁷ represents a hydrogen atom, ahalogen atom, C₁₋₄ alkyl, C₁₋₄ alkoxy, or C₁₋₄ alkylthio, R⁶²⁶ and R⁶²⁷may combine with a carbon atom attached thereto to form an unsaturatedsix-membered carbocyclic or heterocyclic group, R⁶²⁸ represents ahydrogen atom, a halogen atom, nitro, cyano, C₁₋₆ alkyl in which thealkyl group is optionally substituted by hydroxyl; phenyl; aminooptionally substituted by C₁₋₄ alkyl; C₁₋₄ alkylcarbonyloxy; or asaturated or unsaturated six-membered heterocyclic group optionallysubstituted by C₁₋₄ alkyl, C₁₋₈ alkoxy, C₁₋₄ alkylcarbonyl, C₂₋₆ alkenyloptionally substituted by a saturated or unsaturated six-memberedcarbocyclic group, C₂₋₆ alkynyl optionally substituted by C₁₋₂alkylsilyl, a saturated or unsaturated three- to eight-memberedcarbocyclic oxy group, a saturated or unsaturated six-memberedcarbocyclic carbonyl or heterocyclic carbonyl group optionallysubstituted by C₁₋₄ alkyl, or a saturated or unsaturated three- toeight-membered carbocyclic or heterocyclic group in which thecarbocyclic or heterocyclic group is optionally substituted by hydroxyl;cyano; a halogen atom; C₁₋₄ alkoxy; phenyloxy; C₁₋₄ alkylcarbonyl; aminooptionally substituted by C₁₋₄ alkyl or C₁₋₄ alkylcarbonyl;aminocarbonyl optionally substituted by C₁₋₄ alkyl; or C₁₋₄ alkyloptionally substituted by hydroxyl or a halogen atom.
 40. The compoundaccording to claim 39, wherein R⁶²⁸ represents a saturated orunsaturated four- to seven-membered carbocyclic or heterocyclic group inwhich the carbocyclic or heterocyclic group is optionally substituted byhydroxyl; cyano; a halogen atom; C₁₋₄ alkoxy; phenyloxy; C₁₋₄alkylcarbonyl; amino optionally substituted by C₁₋₄ alkyl or C₁₋₄alkylcarbonyl; aminocarbonyl optionally substituted by C₁₋₄ alkyl; orC₁₋₄ alkyl optionally substituted by hydroxyl or a halogen atom.
 41. Thecompound according to claim 1 or pharmaceutically acceptable salt orsolvate thereof, wherein formula (I) is represented by formula (700):

wherein X represents N, Z represents —O—, —NH—, —S—, or —C(═O)—, R⁷⁰¹and R⁷⁰², which may be the same or different, represent any groupselected from C₁₋₆ alkyl, R⁷²⁹ represents a hydrogen atom, R⁷³⁰represents a hydrogen atom or C₁₋₄ alkyl, and R⁷³¹ and R⁷³² combine witha carbon atom attached thereto to form an unsaturated five- orsix-membered carbocyclic or heterocyclic group in which the carbocyclicor heterocyclic group is optionally substituted by a halogen atom orC₁₋₄ alkyl.
 42. The compound according to claim 41, wherein Z represents—O— and R⁷⁰¹ and R⁷⁰² represent methyl.
 43. The compound according toclaim 1, represented by formula (800), or a pharmaceutically acceptablesalt or solvate thereof:

wherein X represents N, Z represents —O—, —NH—, —S—, or —C(═O)—, R⁸⁰¹and R⁸⁰², which may be the same or different, represent any groupselected from C₁₋₆ alkyl, R⁸³³ and R⁸³⁴ represent a hydrogen atom, andR⁸³⁵ and R⁸³⁶ combine with a carbon atom attached thereto to form anunsaturated five- or six-membered carbocyclic or heterocyclic group. 44.The compound according to claim 43, wherein Z represents —O— or —S—,R⁸⁰¹ and R⁸⁰² represent methyl, R⁸³⁵ and R⁸³⁶ combine with a carbon atomattached thereto to form phenyl.
 45. The compound according to claim 1or pharmaceutically acceptable salt or solvate thereof, wherein formula(I) is represented by formula (900):

wherein X represents N, Z represents —O—, —NH—, —S—, or —C(═O)—, R⁹⁰¹and R⁹⁰², which may be the same or different, represent any groupselected from C₁₋₆ alkyl R⁹²⁰, R⁹²¹, R⁹²³, and R⁹²⁴, which may be thesame or different, represent a hydrogen atom, a halogen atom, C₁₋₁₀alkyl optionally substituted by hydroxyl, a saturated or unsaturatedfive- or six-membered carbocyclic or heterocyclic group, C₁₋₈ alkoxy,C₂₋₆ alkenyl optionally substituted by C₁₋₄ alkyl, C₁₋₄ alkoxy, anoxygen atom or phenyl, phenylcarbonyl optionally substituted by C₁₋₄alkyl, amino optionally substituted by phenyl, nitro, or a saturated orunsaturated five- or six-membered carbocyclic or heterocyclic group inwhich the carbocyclic or heterocyclic group is optionally substituted byC₁₋₆ alkyl, provided that at least one of R⁹²⁰ and R⁹²⁴ is selected froma group other than a hydrogen atom, R⁹²² represents C₁₋₁₀ alkyloptionally substituted by hydroxyl, a saturated or unsaturatedsix-membered carbocyclic or heterocyclic group, C₁₋₈ alkoxy, aminooptionally substituted by phenyl, nitro, or a saturated or unsaturatedfive- or six-membered carbocyclic or heterocyclic group in which thecarbocyclic or heterocyclic group is optionally substituted by C₁₋₆alkyl, and R⁹²¹ and R⁹²², or R⁹²² and R⁹²³ may combine with a carbonatom attached thereto to form a saturated or unsaturated five- orsix-membered carbocyclic or heterocyclic group in which the carbocyclicor heterocyclic group is optionally substituted by a halogen atom, C₁₋₄alkyl, C₁₋₄ alkylcarbonyl, C₁₋₆ alkoxycarbonyl, or an oxygen atom, andthe carbocyclic or heterocyclic group may condense with anothersaturated or unsaturated five- or six-membered carbocyclic orheterocyclic group to form a tricyclic group together with thesix-membered carbocyclic ring of formula (c).
 46. The compound accordingto claim 45, wherein at least one of R⁹²⁰ and R⁹²⁴ is selected from agroup other than a hydrogen atom, and R⁹²¹ and R⁹²², or R⁹²² and R⁹²³may combine with a carbon atom attached thereto to form a saturated orunsaturated five- or six-membered carbocyclic or heterocyclic group inwhich the carbocyclic or heterocyclic group is optionally substituted bya halogen atom, C₁₋₄ alkyl, C₁₋₄ alkylcarbonyl, C₁₋₆ alkoxycarbonyl, oran oxygen atom.
 47. A pharmaceutical composition comprising as an activeingredient the compound according to claim 1 or a pharmaceuticallyacceptable salt or solvate thereof; and a pharmaceutically acceptablecarrier. 48-53. (canceled)
 54. A method for treating a disease for whichTGFβ inhibition is effective therapeutically or prophylactically,comprising the step of administering a therapeutically orprophylactically effective amount of the compound according to claim 1or a pharmaceutically acceptable salt or solvate thereof to a patientwho should undergo therapy of a disease for which inhibition activity iseffective therapeutically or prophylactically.
 55. The method accordingto claim 54, wherein the disease for which TGFβ inhibition is effectivetherapeutically or prophylactically is a disease involving fibrosis ofan organ or a tissue.
 56. The method according to claim 54, wherein thedisease for which TGFβ inhibition is effective therapeutically orprophylactically is chronic renal disease, acute renal disease, hepaticfibrosis, cirrhosis, pulmonary fibrosis, scleroderma, wound healing,arthritis, congestive cardiac disease, ulcer, ocular disorder, corneadisorder, diabetic nephropathy, peritoneal sclerosis, arterialsclerosis, peritoneal adhesion, or subdermal adhesion.
 57. The methodaccording to claim 54, wherein the disease for which TGFβ inhibition iseffective therapeutically or prophylactically is a malignant tumor. 58.A method for amplifying cells in vitro, comprising the step of addition,into target cells in vitro, of the compound according to claim 1 or apharmaceutically acceptable salt or solvate thereof in an amounteffective for promoting cell amplification to amplify cells.
 59. Themethod according to claim 58, wherein said target cells arehematopoietic stem cells.
 60. A method for inhibiting the action of TGFβon cells, comprising the step of applying an effective amount of thecompound according to claim 1 to cells present in vitro or in vivo.61-63. (canceled)